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N6-methyladenosine (m6A) is the most abundant internal modification on eukaryotic mRNAs. Demethylation of m6A on mRNA is catalyzed by the enzyme fat mass and obesity-associated protein (FTO), a member of the nonheme Fe(II) and 2-oxoglutarate (2-OG)-dependent family of dioxygenases. FTO activity and m6A-mRNA are dysregulated in multiple diseases including cancers, yet endogenous signaling molecules that modulate FTO activity have not been identified. Here we show that nitric oxide (NO) is a potent inhibitor of FTO demethylase activity by directly binding to the catalytic iron center, which causes global m6A hypermethylation of mRNA in cells and results in gene-specific enrichment of m6A on mRNA of NO-regulated transcripts. Both cell culture and tumor xenograft models demonstrated that endogenous NO synthesis can regulate m6A-mRNA levels and transcriptional changes of m6A-associated genes. These results build a direct link between NO and m6A-mRNA regulation and reveal a novel signaling mechanism of NO as an endogenous regulator of the epitranscriptome.

Nitrite represents an endocrine reserve of bioavailable nitric oxide (NO) that mediates a number of physiological responses including conferral of cytoprotection after ischemia/reperfusion (I/R). It has long been known that nitrite can react with non-heme iron to form dinitrosyliron complexes (DNIC). However, it remains unclear how quickly nitrite-dependent DNIC form in vivo, whether formation kinetics differ from that of NO-dependent DNIC, and whether DNIC play a role in the cytoprotective effects of nitrite. Here we demonstrate that chronic but not acute nitrite supplementation increases DNIC concentration in the liver and kidney of mice. Although DNIC have been purported to have antioxidant properties, we show that the accumulation of DNIC in vivo is not associated with nitrite-dependent cytoprotection after hepatic I/R. Further, our data in an isolated mitochondrial model of anoxia/reoxygenation show that while NO and nitrite demonstrate similar S-nitrosothiol formation kinetics, DNIC formation is significantly greater with NO and associated with mitochondrial dysfunction as well as inhibition of aconitase activity. These data are the first to directly compare mitochondrial DNIC formation by NO and nitrite. This study suggests that nitrite-dependent DNIC formation is a physiological consequence of dietary nitrite. The data presented herein implicate mitochondrial DNIC formation as a potential mechanism underlying the differential cytoprotective effects of nitrite and NO after I/R, and suggest that DNIC formation is potentially responsible for the cytotoxic effects observed at high NO concentrations.

Nitric oxide (•NO, nitrogen monoxide) is one of the most unique biological signaling molecules associated with a multitude of physiologic and pathological conditions. In order to fully appreciate its numerous roles, it is essential to understand its basic biochemical properties. Most signaling effector molecules such as steroids or proteins have a significant life-span and function through classical receptor–ligand interactions. •NO, however, is a short-lived free-radical gas that only reacts with two types of molecules under biological conditions; metals and other free radicals. These simple interactions can lead to a myriad of complex intermediates which in turn have their own phenotypic effects. For these reasons, responses to •NO often appear to be random or contradictory when outcomes are compared across various experimental settings. This article will serve as a brief overview of the chemical, biological, and microenvironmental factors that dictate •NO signaling with an emphasis on •NO metabolism. The prominent role that oxygen (dioxygen, O2) plays in •NO metabolism and how it influences the biological effects of •NO will be highlighted. This information and these concepts are intended to help students and investigators think about the interpretation of data from experiments where biological effects of •NO are being elucidated. Keywords: Nitric oxide, Diffusion, Oxygen, Metabolism, Half-life, Signaling

Nitric oxide (·NO) is a biologically important short-lived free radical signaling molecule. Both the enzymatic synthesis and the predominant forms of cellular metabolism of ·NO are oxygen-dependent. For these reasons, changes in local oxygen concentrations can have a profound influence on steady-state ·NO concentrations. Many proteins are regulated by ·NO in a concentration-dependent manner, but their responses are elicited at different thresholds. Using soluble guanylyl cyclase (sGC) and p53 as model ·NO-sensitive proteins, we demonstrate that their concentration-dependent responses to ·NO are a function of the O2 concentration. p53 requires relatively high steady-state ·NO concentrations (>600 nM) to induce its phosphorylation (P-ser-15), whereas sGC responds to low ·NO concentrations (

Middle level teachers and administrators working in small or rural schools often face unique obstacles in implementing recommended middle level practices. From sharing staff and schedules with other school sites, to inappropriate instructional techniques, to a general lack of understanding of the middle level philosophy, these obstacles can be a source of frustration for school leaders and hinder school improvement initiatives. A better understanding of these issues and the discussion of potential solutions will benefit teachers, administrators, and policy makers in improving middle level education in rural communities. By building on the positive characteristics found in rural and smaller schools, as well as identifying and addressing the obstacles encountered at smaller schools, middle level leaders can create and maintain distinctive and effective programs for their students.

DNA methylation at cytosine bases of eukaryotic DNA (5-methylcytosine, 5mC) is a heritable epigenetic mark that can regulate gene expression in health and disease. Enzymes that metabolize 5mC have been well-characterized, yet the discovery of endogenously produced signaling molecules that regulate DNA methyl-modifying machinery have not been described. Herein, we report that the free radical signaling molecule nitric oxide (NO) can directly inhibit the Fe(II)/2-OG-dependent DNA demethylases ten-eleven translocation (TET) and human AlkB homolog 2 (ALKBH2). Physiologic NO concentrations reversibly inhibited TET and ALKBH2 demethylase activity by binding to the mononuclear non-heme iron atom which formed a dinitrosyliron complex (DNIC) preventing cosubstrates (2-OG and O 2 ) from binding. In cancer cells treated with exogenous NO, or cells endogenously synthesizing NO, there was a global increase in 5mC and 5-hydroxymethylcytosine (5hmC) in DNA, the substrates for TET, that could not be attributed to increased DNA methyltransferase activity. 5mC was also elevated in NO-producing cell-line-derived mouse xenograft and patient-derived xenograft tumors. Genome-wide DNA methylome analysis of cells chronically treated with NO (10 days) demonstrated enrichment of 5mC and 5hmC at gene-regulatory loci which correlated to changes in the expression of NO-regulated tumor-associated genes. Regulation of DNA methylation is distinctly different from canonical NO signaling and represents a novel epigenetic role for NO., Competing Interests: Competing interests J.C.C. is the sole inventor on patent application no. 10420838 entitled “Methods for treating cancer using iNOS-inhibitory compositions” held by Houston Methodist Hospital.

Power outages in the U.S. affect many firms' economic activity and are likely to result in downstream supply chain disruptions. This paper examines the impact of power disturbances in the supply chain for four industries: manufacturing, durable goods manufacturing, nondurable goods manufacturing, and total private industry. This indirect impact includes the losses at downstream firms that might not receive supplies on time due to disturbances at their suppliers' facilities. This is measured using observations of value added before and after power disturbances rather than the more common method of modeling an economy. This paper tests four hypotheses related to the effect of power disturbances with all four of them being supported by the model results. Further, using simulation we estimate the indirect costs of power disturbances. The results suggest that power disturbances have a statistically significant effect on gross domestic product (i.e., value added), particularly in manufacturing where power disturbances in the supply chain had a statistically significant effect. While this industry represents 12.8 % of private industry value added, it experiences 36.8 % of the supply chain losses due to power disturbances, as suggested by the results of the simulation. Power disturbances in the supply chain affected all four industries with nondurable goods being affected the most. This creates a significant disconnect between the stakeholder that invests in reliability in the power grid and the stakeholders that experience the bulk of losses.

Industrial artificial intelligence (IAI) and other analysis tools with obfuscated internal processes are growing in capability and ubiquity within industrial settings. Decision-makers share their concern regarding the objective evaluation of such tools and their impacts at the system level, facility level, and beyond. One application where this style of tool is making a significant impact is in Condition Monitoring Systems (CMSs). This paper addresses the need to evaluate CMSs, a collection of software and devices that alert users to changing conditions within assets or systems of a facility. The presented evaluation procedure uses CMSs as a case study for a broader philosophy evaluating the impacts of IAI tools. CMSs can provide value to a system by forewarning faults, defects, or other unwanted events. However, evaluating CMS value through scenarios that did not occur is rarely easy or intuitive. Further complicating this evaluation are the ongoing investment costs and risks posed by the CMS from imperfect monitoring. To overcome this, an industrial facility needs to regularly and objectively review CMS impacts to justify investments and maintain competitive advantage. This paper's procedure assesses the suitability of a CMS for a system in terms of risk and investment analysis. This risk-based approach uses the changes in the likelihood of good and bad events to quantify CMS value without making any one-time point-wise estimates. Fictional case studies presented in this paper illustrate the procedure and demonstrate its usefulness and validity., Competing Interests: Conflict of Interest There are no conflicts of interest.

Study Objectives: Insomnia is a risk factor for suicidal behavior including attempts and death by suicide. We investigated whether insomnia symptom severity was associated with suicidality and death by suicide in patients with psychiatric disorders., Methods: The sample included 180 deceased patients with psychiatric disorders seen at Weber Human Services between 2008 and 2018 who completed the Outpatient Questionnaire-45.2 (OQ) prior to death. Insomnia symptom severity was assessed using item 41 from the OQ. Manner of death was determined by death records and autopsy reports. History of suicidality was determined through electronic medical records. Cases were grouped into four lifetime categories: non-suicidal (n = 30), suicidal ideation (n = 36), suicide attempt (n = 95), and death by suicide (n = 19). Demographic, medical, and psychiatric features of each group were compared using linear regression. Logistic regression was used to determine whether insomnia symptom severity was associated with lifetime suicidality severity grouping, adjusting for psychiatric disorders commonly linked to suicidality., Results: Lifetime suicidality was associated with sleep problems, fatigue, headaches, and psychiatric disorders (i.e. depressive, personality, and trauma-related disorders). Referenced to the non-suicidal group, greater insomnia symptom severity was significantly associated with suicide attempts and death by suicide, with odds ratios (OR) of OR = 2.67, p = 0.011, and OR = 5.53, p = 0.002, respectively, even after adjusting important psychiatric diagnoses., Conclusions: Results suggest that insomnia symptom severity endorsed during a clinical visit is associated with heightened suicidality, especially suicidal behavior. The presence of insomnia symptoms in patients with psychiatric disorders may indicate risk for suicide and is a target for suicide prevention., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This paper examines the impact of natural and human-made hazards on payroll, GDP, employment, and establishment survival/creation in the year of hazard occurrence in the U.S. economy and more specifically in the U.S. manufacturing/goods producing industry. Many of the papers that examine economic impacts of hazards consider upstream impacts of supply chain disruption. Measures of downstream impacts are often limited, particularly in measuring the short-term impacts. This paper examines how manufacturers and other establishments are impacted, at the industry and total economy level, by a disruption in supplies of goods with low substitutability, which is often referred to as the ripple effect. In this paper, eight models are developed to explore supply chain vulnerability, at the industry-level, to hazard events across geographic areas of the U.S. during the 2005 to 2016 time period. The most severe impacts are due to hazards in the manufacturing/goods industry supply chain, where payroll, GDP, and employment declined 2.9 %, 3.9 %, and 8.6 %, respectively. For all establishments, payroll and employment declined 5.3 % and 3.0 %, respectively. The results further suggest that the compound effect of hazards through the supply chain possibly exceeds that of the local hazard (i.e., direct impact). This can create an incentive misalignment. The establishment that invests in mitigation efforts and experiences the hazard locally does not directly experience the majority of the net benefit. The findings also suggest there is a need to better understand the short-term downstream impacts from all hazards, especially at the aggregated national level., Competing Interests: Conflict of Interest: The authors declare that they have no conflicts of interest.

The costs/benefits associated with investing in advanced maintenance techniques is not well understood. Using data collected from manufacturers, we estimate the national losses due to inadequate maintenance and make comparisons between those that rely on reactive maintenance, preventive maintenance, and predictive maintenance. The total annual costs/losses associated with maintenance is estimated to be on average $222.0 billion, as estimated using Monte Carlo analysis. Respondents were categorized into three groups and compared. The first group is the top 50 % of respondents that rely on reactive maintenance, measured in expenditures. The remaining respondents were split in half based on their reliance on predictive maintenance. The top 50 % of respondents in using reactive maintenance, measured in expenditures, compared to the other respondents suggests that there are substantial benefits of moving away from reactive maintenance toward preventive and/or predictive maintenance. The bottom 50 %, which relies more heavily on predictive and preventive maintenance, had 52.7 % less unplanned downtime and 78.5 % less defects. The comparison between the smaller two groups, which rely more heavily on preventive and predictive maintenance, shows that there is 18.5 % less unplanned downtime and 87.3 % less defects for those that rely more on predictive than preventive.

This paper examines supply chain value added in the US for producing assembly-centric products, which includes machinery, computers, electronics, and transportation equipment, and determines whether costs are disproportionally distributed. The implication being that reductions in resource consumption in some cost areas can disproportionally reduce total resource consumption. Efforts to develop and disseminate innovative solutions to improve efficiency can, therefore, be targeted to these high cost areas, resulting in larger efficiency improvements than might otherwise be achieved. An input-output model is used for this examination and is combined with labor data and data on assets. The top 20 industries, occupations, and industry occupation combinations contributing to production are identified. A sensitivity analysis is conducted on the model using Monte Carlo simulation. The results confirm that costs are disproportionally distributed, having a Gini coefficient of 0.75 for value added and for compensation it is 0.86. Wholesale trade , aircraft manufacturing , and the management of companies and enterprises were the industries with the largest contribution to assembly-centric manufacturing, even when including imports. Energy in the form of electricity and natural gas were discussed separately, but would rank 8 th if compared to the industry rankings. In terms of occupation activities, team assemblers, general and operations managers, and sales representatives were the largest occupations. Public entities might use this model and results to identify efficiency improvement efforts that will have the largest impact on industry per dollar of expenditure.

The US and other national governments invest in research and development to spur competitiveness in their domestic manufacturing industries. However, there are limited studies on identifying the research efforts that will have the largest possible return on investment, resulting in suboptimal returns. Manufacturers commonly measure production time in order to identify areas for efficiency improvement, but this is typically not applied at the national level where efficiency issues may cross between enterprises and industries. Such methods and results can be used to prioritize efficiency improvement efforts at an industry supply-chain level. This paper utilizes data on manufacturing inventory along with data on inter-industry interactions to develop a method for tracking industry-level flow time and identifying bottlenecks in US manufacturing. As a proof of concept, this method is applied to the production of three commodities: aircraft, automobiles/trucks, and computers. The robustness of bottleneck identification is tested utilizing Monte Carlo techniques.

Culturally focused research has gained momentum in many disciplines, including psychology. However, much of this research fails to pay attention to the unconscious dynamics that underlie the study of culture and culturally influenced human beings. Such dynamics may be especially significant when issues of marginalization and oppression are present. Therefore, this paper seeks to contribute a framework for understanding cultural dynamics, especially unconscious cultural dynamics, within depth psychological qualitative research influenced by Jungian and post-Jungian scholarship. Inquiry that is approached with a commitment to making the unconscious conscious seeks to empower and liberate not only the subject/object studied but also the researchers themselves. Following a brief review of multiculturalism in the context of analytically informed psychology, this paper offers several case examples that focus on researchers' integration of awareness of the cultural unconscious in their study of cultural beings and topics., (© 2016, The Society of Analytical Psychology.)

There are three primary aspects to the economics of additive manufacturing: measuring the value of goods produced, measuring the costs and benefits of using the technology, and estimating the adoption and diffusion of the technology. This paper provides an updated estimate of the value of goods produced. It then reviews the literature on additive manufacturing costs and identifies those instances in the literature where this technology is cost effective. The paper then goes on to propose an approach for examining and understanding the societal costs and benefits of this technology both from a monetary viewpoint and a resource consumption viewpoint. The final section discusses the trends in the adoption of additive manufacturing. Globally, there is an estimated $667 million in value added produced using additive manufacturing, which equates to 0.01 % of total global manufacturing value added. US value added is estimated as $241 million. Current research on additive manufacturing costs reveals that it is cost effective for manufacturing small batches with continued centralized production; however, with increased automation distributed production may become cost effective. Due to the complexities of measuring additive manufacturing costs and data limitations, current studies are limited in their scope. Many of the current studies examine the production of single parts and those that examine assemblies tend not to examine supply chain effects such as inventory and transportation costs along with decreased risk to supply disruption. The additive manufacturing system and the material costs constitute a significant portion of an additive manufactured product; however, these costs are declining over time. The current trends in costs and benefits have resulted in this technology representing 0.02 % of the relevant manufacturing industries in the US; however, as the costs of additive manufacturing systems decrease, this technology may become widely adopted and change the supplier, manufacturer, and consumer interactions. An examination in the adoption of additive manufacturing reveals that for this technology to exceed $4.4 billion in 2020, $16.0 billion in 2025, and $196.8 billion in 2035 it would need to deviate from its current trends of adoption.

Prolonged exposure to hyperoxia results in acute lung injury (ALI), accompanied by a significant elevation in the levels of proinflammatory cytokines and leukocyte infiltration in the lungs. However, the mechanisms underlying hyperoxia-induced proinflammatory ALI remain to be elucidated. In this study, we investigated the role of the proinflammatory cytokine high mobility group box protein 1 (HMGB1) in hyperoxic inflammatory lung injury, using an adult mouse model. The exposure of C57BL/6 mice to ≥99% O2 (hyperoxia) significantly increased the accumulation of HMGB1 in the bronchoalveolar lavage fluids (BALF) prior to the onset of severe inflammatory lung injury. In the airways of hyperoxic mice, HMGB1 was hyperacetylated and existed in various redox forms. Intratracheal administration of recombinant HMGB1 (rHMGB1) caused a significant increase in leukocyte infiltration into the lungs compared to animal treated with a non-specific peptide. Neutralizing anti-HMGB1 antibodies, administrated before hyperoxia significantly attenuated pulmonary edema and inflammatory responses, as indicated by decreased total protein content, wet/dry weight ratio, and numbers of leukocytes in the airways. This protection was also observed when HMGB1 inhibitors were administered after the onset of the hyperoxic exposure. The aliphatic antioxidant, ethyl pyruvate (EP), inhibited HMGB1 secretion from hyperoxic macrophages and attenuated hyperoxic lung injury. Overall, our data suggest that HMGB1 plays a critical role in mediating hyperoxic ALI through the recruitment of leukocytes into the lungs. If these results can be translated to humans, they suggest that HMGB1 inhibitors provide treatment regimens for oxidative inflammatory lung injury in patients receiving hyperoxia through mechanical ventilation.