Import of cytochrome c into mitochondria

The covalent attachment of heme to apocytochrome c, and therefore the import of cytochrome c into mitochondria, is dependent on both NADH plus a cytosolic cofactor that has been identified to be FMN or FAD. NADH in concert with flavin nucleotides mediates the reduction of heme. Heme in the reduced state is a prerequisite for its covalent attachment to apocytochrome c by the enzyme cytochrome c heme lyase and thus for subsequent translocation of cytochrome c across the outer mitochondrial membrane during import

Information needs and institutional development

Michael W. Nicholson; Armine R. Mirzoya

Privacy and Accountability in Black-Box Medicine

Black-box medicine—the use of big data and sophisticated machine learning techniques for health-care applications—could be the future of personalized medicine. Black-box medicine promises to make it easier to diagnose rare diseases and conditions, identify the most promising treatments, and allocate scarce resources among different patients. But to succeed, it must overcome two separate, but related, problems: patient privacy and algorithmic accountability. Privacy is a problem because researchers need access to huge amounts of patient health information to generate useful medical predictions. And accountability is a problem because black-box algorithms must be verified by outsiders to ensure they are accurate and unbiased, but this means giving outsiders access to this health information. This article examines the tension between the twin goals of privacy and accountability and develops a framework for balancing that tension. It proposes three pillars for an effective system of privacy-preserving accountability: substantive limitations on the collection, use, and disclosure of patient information; independent gatekeepers regulating information sharing between those developing and verifying black-box algorithms; and information-security requirements to prevent unintentional disclosures of patient information. The article examines and draws on a similar debate in the field of clinical trials, where disclosing information from past trials can lead to new treatments but also threatens patient privacy

Manufacturing Barriers to Biologics Competition and Innovation

As finding breakthrough small-molecule drugs gets harder, drug companies are increasingly turning to “large molecule” biologics. Although biologics represent many of the most promising new therapies for previously intractable diseases, they are extremely expensive. Moreover, the pathway for generic-type competition set up by Congress in 2010 is unlikely to yield significant cost savings. In this Article, we provide a fresh diagnosis of, and prescription for, this major public policy problem. We argue that the key cause is pervasive trade secrecy in the complex area of biologics manufacturing. Under the current regime, this trade secrecy, combined with certain features of FDA regulation, not only creates high barriers to entry of indefinite duration but also undermines efforts to advance fundamental knowledge. In sharp contrast, offering incentives for information disclosure to originator manufacturers would leverage the existing interaction of trade secrecy and the regulatory state in a positive direction. Although trade secrecy, particularly in complex areas like biologics manufacturing, often involves tacit knowledge that is difficult to codify and thus transfer, in this case regulatory requirements that originator manufacturers submit manufacturing details have already codified the relevant tacit knowledge. Incentivizing disclosure of these regulatory submissions would not only spur competition but it would provide a rich source of information upon which additional research, including fundamental research into the science of manufacturing, could build. In addition to provide fresh diagnosis and prescription in the specific area of biologics, the Article contributes to more general scholarship on trade secrecy and tacit knowledge. Prior scholarship has neglected the extent to which regulation can turn tacit knowledge not only into codified knowledge but into precisely the type of codified knowledge that is most likely to be useful and accurate. The Article also draws a link to the literature on adaptive regulation, arguing that greater regulatory flexibility is necessary and that more fundamental knowledge should spur flexibility. A vastly shortened version of the central argument that manufacturing trade secrecy hampers biosimilar development was published at 348 Science 188 (2015), available online

Nudging the FDA

[Excerpt] The FDA’s regulation of drugs is frequently the subject of policy debate, with arguments falling into two camps. On the one hand, a libertarian view of patients and the health care system holds high the value of consumer choice. Patients should get all the information and the drugs they want; the FDA should do what it can to enforce some basic standards but should otherwise get out of the way. On the other hand, a paternalist view values the FDA’s role as an expert agency standing between patients and a set of potentially dangerous drugs and potentially unscrupulous or at least insufficiently careful drug companies. We lay out here some of the ways the FDA regulates drugs, including some normally left out of the debate, and suggest a middle ground between libertarian and paternalistic approaches focused on correcting information asymmetry and aligning incentives.

Biogenesis of cytochrome c1

The biogenesis of cytochrome c1 involves a number of steps including: synthesis as a precursor with a bipartite signal sequence, transfer across the outer and inner mitochondrial membranes, removal of the first part of the presequence in the matrix, reexport to the outer surface of the inner membrane, covalent addition of heme, and removal of the remainder of the presequence. In this report we have focused on the steps of heme addition, catalyzed by cytochrome c1 heme lyase, and of proteolytic processing during cytochrome c1 import into mitochondria. Following translocation from the matrix side to the intermembrane-space side of the inner membrane, apocytochrome c1 forms a complex with cytochrome c1 heme lyase, and then holocytochrome c1 formation occurs. Holocytochrome c1 formation can also be observed in detergent-solubilized preparations of mitochondria, but only after apocytochrome c1 has first interacted with cytochrome c1 heme lyase to produce this complex. Heme linkage takes place on the intermembrane- space side of the inner mitochondrial membrane and is dependent on NADH plus a cytosolic cofactor that can be replaced by flavin nucleotides. NADH and FMN appear to be necessary for reduction of heme prior to its linkage to apocytochrome c1. The second proteolytic processing of cytochrome c1 does not take place unless the covalent linkage of heme to apocytochrome c1 precedes it. On the other hand, the cytochrome c1 heme lyase reaction itself does not require that processing of the cytochrome c1 precursor to intermediate size cytochrome c1 takes place first. In conclusion, cytochrome c1 heme lyase catalyzes an essential step in the import pathway of cytochrome c1, but it is not involved in the transmembrane movement of the precursor polypeptide. This is in contrast to the case for cytochrome c in which heme addition is coupled to its transport directly across the outer membrane into the intermembrane space

Financial Performance Value-Added Dairy Operations in New York, Vermont and Wisconsin

Federal, state and local governments have funded various efforts to support value added agriculture, often implicitly assuming that the enterprises would be profitable and that the transition from commodity producer to producer-processor-marketer-distributor would be relatively easy. Some analysts (e.g., Streeter and Bills; 2003a, 2003b) have questioned both of these assumptions, noting that available aggregate data do not allow assessment of the financial performance of value-added enterprises. Our study collected detailed financial information from 27 value-added dairy enterprises with cows, goats or sheep in three states. These businesses processed and marketed cheese, fluid milk products and yogurt; 17 had begun processing during the previous three years. The financial information was used to develop income statements and balance sheets for both the milk production and the dairy processing and marketing enterprises. Our results suggest that value-added dairy is not a panacea: despite much higher revenues per unit milk produced or processed, mean net income for the processing enterprise and for the combined milk production and processing business were modest at best and often negative. More than half of the on-farm processors had negative net incomes from processing, and seven processing enterprises had negative net worth. On average, returns per cwt milk processed were $90 per cwt and$209 per cwt (for cow and goat/sheep milk producers, respectively) lower than the full economic costs of production and processing.small-scale dairy processing, value added, financial performance, profitability, Agricultural Finance,