Terpenoids, compounds found in all domains of life, represent the largest class of natural products with essential roles in their hosts. All terpenoids originate from the five-carbon building blocks, ...isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP), which can be derived from the mevalonic acid (MVA) and methylerythritol phosphate (MEP) pathways. The absence of two components of the MVA pathway from archaeal genomes led to the discovery of an alternative MVA pathway with isopentenyl phosphate kinase (IPK) catalyzing the final step, the formation of IPP. Despite the fact that plants contain the complete classical MVA pathway, IPK homologs were identified in every sequenced green plant genome. Here, we show that IPK is indeed a member of the plant terpenoid metabolic network. It is localized in the cytosol and is coexpressed with MVA pathway and downstream terpenoid network genes.In planta,IPK acts in parallel with the MVA pathway and plays an important role in regulating the formation of both MVA and MEP pathway-derived terpenoid compounds by controlling the ratio of IP/DMAP to IPP/DMAPP. IP and DMAP can also competitively inhibit farnesyl diphosphate synthase. Moreover, we discovered a metabolically available carbon source for terpenoid formation in plants that is accessible viaIPKoverexpression. This metabolite reactivation approach offers new strategies for metabolic engineering of terpenoid production.
Use of salt substitutes containing potassium chloride is a potential strategy to reduce sodium intake, increase potassium intake, and thereby lower blood pressure and prevent the adverse consequences ...of high blood pressure. In this review, we describe the rationale for using potassium-enriched salt substitutes, summarize current evidence on the benefits and risks of potassium-enriched salt substitutes and discuss the implications of using potassium-enriched salt substitutes as a strategy to lower blood pressure. A benefit of salt substitutes that contain potassium chloride is the expected reduction in dietary sodium intake at the population level because of reformulation of manufactured foods or replacement of sodium chloride added to food during home cooking or at the dining table. There is empirical evidence that replacement of sodium chloride with potassium-enriched salt substitutes lowers systolic and diastolic blood pressure (average net Δ 95% CI in mm Hg–5.58 –7.08 to –4.09 and –2.88 –3.93 to –1.83, respectively). The risks of potassium-enriched salt substitutes include a possible increased risk of hyperkalemia and its principal adverse consequencesarrhythmias and sudden cardiac death, especially in people with conditions that impair potassium excretion such as chronic kidney disease. There is insufficient evidence regarding the effects of potassium-enriched salt substitutes on the occurrence of hyperkalemia. There is a need for additional empirical research on the effect of increasing dietary potassium and potassium-enriched salt substitutes on serum potassium levels and the risk of hyperkalemia, as well as for robust estimation of the population-wide impact of replacing sodium chloride with potassium-enriched salt substitutes.
Plant genomes encode isopentenyl phosphate kinases (IPKs) that reactivate isopentenyl phosphate (IP) via ATP-dependent phosphorylation, forming the primary metabolite isopentenyl diphosphate (IPP) ...used generally for isoprenoid/terpenoid biosynthesis. Therefore, the existence of IPKs in plants raises unanswered questions concerning the origin and regulatory roles of IP in plant terpenoid metabolism. Here, we provide genetic and biochemical evidence showing that IP forms during specific dephosphorylation of IPP catalysed by a subset of Nudix superfamily hydrolases. Increasing metabolically available IP by overexpression of a bacterial phosphomevalonate decarboxylase (MPD) in Nicotiana tabacum resulted in significant enhancement in both monoterpene and sesquiterpene production. These results indicate that perturbing IP metabolism results in measurable changes in terpene products derived from both the methylerythritol phosphate (MEP) and mevalonate (MVA) pathways. Moreover, the unpredicted peroxisomal localization of bacterial MPD led us to discover that the step catalysed by phosphomevalonate kinase (PMK) imposes a hidden constraint on flux through the classical MVA pathway. These complementary findings fundamentally alter conventional views of metabolic regulation of terpenoid metabolism in plants and provide new metabolic engineering targets for the production of high-value terpenes in plants.
Collective narcissism—a phenomenon in which individuals show excessively high regard for their own group—is ubiquitous in studies of small groups. We examined how Americans from the 50 U.S. states (N ...= 2,898) remembered U.S. history by asking them, “In terms of percentage, what do you think was your home state’s contribution to the history of the United States?” The mean state estimates ranged from 9% (Iowa) to 41% (Virginia), with the total contribution for all states equaling 907%, indicating strong collective narcissism. In comparison, ratings provided by nonresidents for states were much lower (but still high). Surprisingly, asking people questions about U.S. history before they made their judgment did not lower estimates. We argue that this ethnocentric bias is due to ego protection, selective memory retrieval processes involving the availability heuristic, and poor statistical reasoning. This study shows that biases that influence individual remembering also influence collective remembering.
Classification of sexual assault varies based on the characteristics of the victim, perpetrator, and event. However, most studies focus on the individual characteristics of participants asked to ...classify the assault, the victims’ characteristics, or the event; few have examined variations in the perpetrator. Therefore, this study examined whether the occupation of the perpetrator affected the classification of the event as sexual assault. Participants included a primarily White female sample of undergraduate students (n = 401) at a south-Atlantic university. They completed a paper-and-pencil survey containing an ambiguous sexual assault encounter where the occupation of the perpetrator (athlete, reporter, college student, or politician) was randomly varied. Participants were asked to classify whether the encounter was sexual assault and what an appropriate punishment might be. Additional measures included the Illinois Rape Myth Acceptance Scale (IRMA) and questions about personal experience with sexual assault. Overall, most participants labeled the encounter as sexual assault, indicating that college students are aware of the legal parameters for providing consent. However, this classification occurred differentially based on the occupation of the perpetrator. Participants were most likely to label the athlete as committing sexual assault, followed by the college student, politician, and reporter, respectively. Females and those who reject rape myths were more likely to label the scenario as sexual assault. A “personal apology” and a “sexual rehabilitation program” were the most common punishments selected for the perpetrator. These findings highlight potential concerns and the need for additional training when college students adjudicate sexual assault reports and determine appropriate consequences.
Excess sodium consumption and insufficient potassium intake contribute to high blood pressure and thus increase the risk of heart disease and stroke. In low-sodium salt, a portion of the sodium in ...salt (the amount varies, typically ranging from 10 to 50%) is replaced with minerals such as potassium chloride. Low-sodium salt may be an effective, scalable, and sustainable approach to reduce sodium and therefore reduce blood pressure and cardiovascular disease at the population level. Low-sodium salt programs have not been widely scaled up, although they have the potential to both reduce dietary sodium intake and increase dietary potassium intake. This article proposes a framework for a successful scale-up of low-sodium salt use in the home through four core strategies: availability, awareness and promotion, affordability, and advocacy. This framework identifies challenges and potential solutions within the core strategies to begin to understand the pathway to successful program implementation and evaluation of low-sodium salt use.
The value of utilizing a multigene pharmacogenetic panel to tailor pharmacotherapy is contingent on the prevalence of prescribed medications with an actionable pharmacogenetic association. The ...Clinical Pharmacogenetics Implementation Consortium (CPIC) has categorized over 35 gene‐drug pairs as “level A,” for which there is sufficiently strong evidence to recommend that genetic information be used to guide drug prescribing. The opportunity to use genetic information to tailor pharmacotherapy among adult patients was determined by elucidating the exposure to CPIC level A drugs among 11 Implementing Genomics In Practice Network (IGNITE)‐affiliated health systems across the US. Inpatient and/or outpatient electronic‐prescribing data were collected between January 1, 2011 and December 31, 2016 for patients ≥ 18 years of age who had at least one medical encounter that was eligible for drug prescribing in a calendar year. A median of ~ 7.2 million adult patients was available for assessment of drug prescribing per year. From 2011 to 2016, the annual estimated prevalence of exposure to at least one CPIC level A drug prescribed to unique patients ranged between 15,719 (95% confidence interval (CI): 15,658–15,781) in 2011 to 17,335 (CI: 17,283–17,386) in 2016 per 100,000 patients. The estimated annual exposure to at least 2 drugs was above 7,200 per 100,000 patients in most years of the study, reaching an apex of 7,660 (CI: 7,632–7,687) per 100,000 patients in 2014. An estimated 4,748 per 100,000 prescribing events were potentially eligible for a genotype‐guided intervention. Results from this study show that a significant portion of adults treated at medical institutions across the United States is exposed to medications for which genetic information, if available, should be used to guide prescribing.
Terpenoids are a large and diverse class of plant metabolites that also includes volatile mono- and sesquiterpenes which are involved in biotic interactions of plants. Due to the limited natural ...availability of these terpenes and the tight regulation of their biosynthesis, there is strong interest to introduce or enhance their production in crop plants by metabolic engineering for agricultural, pharmaceutical and industrial applications. While engineering of monoterpenes has been quite successful, expression of sesquiterpene synthases in engineered plants frequently resulted in production of only minor amounts of sesquiterpenes. To identify bottlenecks for sesquiterpene engineering in plants, we have used two nearly identical terpene synthases, snapdragon (
Antirrhinum majus
) nerolidol/linalool synthase-1 and -2 (AmNES/LIS-1/-2), that are localized in the cytosol and plastids, respectively. Since these two bifunctional terpene synthases have very similar catalytic properties with geranyl diphosphate (GPP) and farnesyl diphosphate (FPP), their expression in target tissues allows indirect determination of the availability of these substrates in both subcellular compartments. Both terpene synthases were expressed under control of the ripening specific
PG
promoter in tomato fruits, which are characterized by a highly active terpenoid metabolism providing precursors for carotenoid biosynthesis. As
AmNES/LIS-2
fruits produced the monoterpene linalool,
AmNES/LIS-1
fruits were found to exclusively produce the sesquiterpene nerolidol. While nerolidol emission in
AmNES/LIS-1
fruits was 60- to 584-fold lower compared to linalool emission in
AmNES/LIS-2
fruits, accumulation of nerolidol-glucosides in
AmNES/LIS-1
fruits was 4- to 14-fold lower than that of linalool-glucosides in
AmNES/LIS-2
fruits. These results suggest that only a relatively small pool of FPP is available for sesquiterpene formation in the cytosol. To potentially overcome limitations in sesquiterpene production, we transiently co-expressed the key pathway-enzymes hydroxymethylglutaryl-CoA reductase (HMGR) and 1-deoxy-D-xylulose 5-phosphate synthase (DXS), as well as the regulator isopentenyl phosphate kinase (IPK). While HMGR and IPK expression increased metabolic flux toward nerolidol formation 5.7- and 2.9-fold, respectively, DXS expression only resulted in a 2.5-fold increase.
Catnip or catmint (
spp.) is a flowering plant in the mint family (Lamiaceae) famed for its ability to attract cats. This phenomenon is caused by the compound nepetalactone, a volatile iridoid that ...also repels insects. Iridoids are present in many Lamiaceae species but were lost in the ancestor of the Nepetoideae, the subfamily containing
. Using comparative genomics, ancestral sequence reconstructions, and phylogenetic analyses, we probed the re-emergence of iridoid biosynthesis in
. The results of these investigations revealed mechanisms for the loss and subsequent re-evolution of iridoid biosynthesis in the
lineage. We present evidence for a chronology of events that led to the formation of nepetalactone biosynthesis and its metabolic gene cluster. This study provides insights into the interplay between enzyme and genome evolution in the origins, loss, and re-emergence of plant chemical diversity.
Objective Systemic sclerosis (SSc) is a rare, chronic, autoimmune disorder associated with disability, diminished physical function, fatigue, pain, and mental health concerns. We assessed minimal ...detectable changes (MDCs) of the Health Assessment Questionnaire‐Disability Index (HAQ‐DI), Patient Reported Outcomes Measurement Information System‐29 Profile version 2.0 (PROMIS‐29v2.0) domains, and Patient Health Questionnaire‐8 (PHQ‐8) in SSc. Methods Scleroderma Patient‐centered Intervention Network Cohort participants completed the HAQ‐DI, PROMIS‐29v2.0 domains, and PHQ‐8 at baseline assessments from April 2014 until August 2023. We estimated MDC95 and MDC90 with 95% confidence intervals (CI) generated via the percentile bootstrapping method resampling 1000 times. We compared MDC estimates by age, sex and SSc subtype. Results A total of 2,571 participants were included. Most were female (N = 2,241; 87%), and 38% (N = 976) had diffuse SSc. Mean (SD) age was 54.9 (12.7) years and duration since onset of first non‐Raynaud phenomenon symptom 10.8 (8.7) years. MDC95 estimate was 0.41 points (95% CI: 0.40 to 0.42) for the HAQ‐DI, between 4.88 points (95% CI: 4.72 to 5.05) and 9.02 points (95% CI: 8.80 to 9.23) for the 7 PROMIS‐29v2.0 domains, and 5.16 points (95% CI: 5.06 to 5.26) for the PHQ‐8. MDC95 estimates were not materially different across subgroups. Conclusion MDC95 and MDC90 estimates were precise and similar across age, sex and SSc subtype groups. HAQ‐DI MDC95 and MDC90 were substantially larger than previous estimates of HAQ‐DI minimal important difference from several small studies. Minimally important differences of all measures should be evaluated in large studies using anchor‐based methods.
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