Pharmacogenetics of analgesic drugs

• Individual variability in pain perception and differences in the efficacy of analgesic drugs are complex phenomena and are partly genetically predetermined. • Analgesics act in various ways on the peripheral and central pain pathways and are regarded as one of the most valuable but equally dangerous groups of medications. • While pharmacokinetic properties of drugs, metabolism in particular, have been scrutinised by genotype–phenotype correlation studies, the clinical significance of inherited variants in genes governing pharmacodynamics of analgesics remains largely unexplored (apart from the µ-opioid receptor). • Lack of replication of the findings from one study to another makes meaningful personalised analgesic regime still a distant future. • This narrative review will focus on findings related to pharmacogenetics of commonly used analgesic medications and highlight authors’ views on future clinical implications of pharmacogenetics in the context of pharmacological treatment of chronic pain

The Hansenula polymorpha PER8 Gene Encodes a Novel Peroxisomal Integral Membrane Protein Involved in Proliferation

We previously described the isolation of mutants of the methylotrophic yeast Hansenula polymorpha that are defective in peroxisome biogenesis. Here, we describe the characterization of one of these mutants, per8, and the cloning of the PER8 gene. In either methanol or methylamine medium, conditions that normally induce the organdies, per8 cells contain no peroxisome-like structures and peroxisomal enzymes are located in the cytosol. The sequence of PER8 predicts that its product (Per8p) is a novel polypeptide of 34 kD, and antibodies against Per8p recognize a protein of 31 kD. Analysis of the primary sequence of Per8p revealed a 39-amino-acid cysteine-rich segment with similarity to the C3HC4 family of zinc-finger motifs. Overexpression of PER8 results in a markedly enhanced increase in peroxisome numbers. We show that Per8p is an integral membrane protein of the peroxisome and that it is concentrated in the membranes of newly formed organdies. We propose that Per8p is a component of the molecular machinery that controls the proliferation of this organelle.

Analysis of alternative hedging strategies for backgrounding feeder calves in Tennessee

This research evaluated various futures market hedging strategies for feeder cattle backgrounding operations to determine their impact on level and variability of net returns. Improving overall net returns and avoiding risk associated with adverse cash price movements were assumed objectives for the cattle producer backgrounding feeder steers. The hedging strategies were simulated with the use of models represent-ing the typical Tennessee producer\u27s summer and winter feeder cattle backgrounding operations during the 1972-79 period. The strategies simulated included variations of basic, moving average, and point-and-figure analysis hedging strategies and the typical cash sale. The mean and variance of net returns were used as criteria for comparing the effectiveness of the strategies simulated. The primary results of the simulations showed that selective hedging could give larger mean net return and lower variance of net return than the cash market. The basic hedging strategies appeared to perform well when the producer began backgrounding steers in the spring and marketed them in the fall. In almost every observation, the moving average and point-and-figure hedging strategies were superior to the cash market by yielding higher mean net returns with lower variances. Assuming similar production and market conditions to those of the simulation period, the results of this study indicate that a producer can effectively increase his mean net returns with smaller risk compared to the cash market when utilizing the superior selective hedging strategies discussed in this study

Adult Children\u27s Perceptions Of Critical Caregiving Conversations With Their Aging Parents: A Pilot Study

The purpose of this qualitative pilot study was to describe adult children\u27s perceptions of critical caregiving conversations between themselves and their aging parents; barriers to these conversations; factors that facilitate these conversations; and the support from health care providers that adult children believe would help facilitate critical caregiving conversations between themselves and their aging parents. The overall purpose was to increase understanding of family communication processes that promote health as families age. Focus group interviews using a semi-structured interview guide were conducted with 16 adult children with caregiving experience of their aging parents. Data analysis was conducted utilizing Leininger\u27s phases of Ethnonursing analysis and facilitated by use of QSR NVivo software for qualitative data analysis. Three themes emerged from the data: (1) navigation of caregiving in aging families, (2) negotiation of caregiving in aging families, and (3) coordination of caregiving in aging families. Study findings indicate the need to engage families and communities together as they navigate, negotiate, and coordinate caregiving conversations with aging adults. The findings of this study can be used for further nursing research on factors that influence family caregiving communication, and help nurses more effectively target communication interventions within the wider community

Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules That Affect Aging Pathways and Extend Caenorhabditis elegans' Lifespan.

Increased resistance to environmental stress at the cellular level is correlated with the longevity of long-lived mutants and wild-animal species. Moreover, in experimental organisms, screens for increased stress resistance have yielded mutants that are long-lived. To find entry points for small molecules that might extend healthy longevity in humans, we screened ∼100,000 small molecules in a human primary-fibroblast cell line and identified a set that increased oxidative-stress resistance. Some of the hits fell into structurally related chemical groups, suggesting that they may act on common targets. Two small molecules increased C. elegans' stress resistance, and at least 9 extended their lifespan by ∼10-50%. We further evaluated a chalcone that produced relatively large effects on lifespan and were able to implicate the activity of two, stress-response regulators, NRF2/skn-1 and SESN/sesn-1, in its mechanism of action. Our findings suggest that screening for increased stress resistance in human cells can enrich for compounds with promising pro-longevity effects. Further characterization of these compounds may reveal new ways to extend healthy human lifespan

Molecular characterization of the Hansenula polymorpha FLD1 gene encoding formaldehyde dehydrogenase

Glutathione-dependent formaldehyde dehydrogenase (FLD) is a key enzyme required for the catabolism of methanol as a carbon source and certain primary amines. such as methylamine as nitrogen sources in methylotrophic yeasts. Here we describe the molecular characterization of the FLD1 gene from the yeast Hansenula polymorpha. Unlike the recently described Pichia pastoris homologue, the H. polymorpha gene does not contain an intron. The predicted FLD1 product (Fld1p) is a protein of 380 amino acids (ca. 41 kDa) with 82% identity to P. pastoris Fld1p, 76% identity to the FLD protein sequence from n-alkane-assimilating yeast Candida maltosa and 63-64% identity to dehydrogenase class III enzymes from humans and other higher eukaryotes. The expression of FLD1 is strictly regulated and can be controlled at two expression levels by manipulation of the growth conditions. The gene is strongly induced under methylotrophic growth conditions; moderate expression is obtained under conditions in which a primary amine, e.g. methylamine, is used as nitrogen source. These properties render the FLD1 promoter of high interest for heterologous gene expression. The availability of the H. polymorpha FLD1 promoter provides an attractive alternative for expression of foreign genes besides the commonly used alcohol oxidase promoter. The sequence has been deposited in the GenBank/NCBI data library under Accession No. AF364077. Copyright (C) 2002 John Wiley Sons, Ltd.</p

Near-Optimality of Finite-Memory Codes and Reinforcement Learning for Zero-Delay Coding of Markov Sources

We study the problem of zero-delay coding of a Markov source over a noisy channel with feedback. We first formulate the problem as a Markov decision process (MDP) where the state is a previous belief term along with a finite memory of channel outputs and quantizers. We then approximate this state by marginalizing over all possible beliefs, so that our policies only use the finite-memory term to encode the source. Under an appropriate notion of predictor stability, we show that such policies are near-optimal for the zero-delay coding problem as the memory length increases. We also give sufficient conditions for predictor stability to hold, and propose a reinforcement learning algorithm to compute near-optimal finite-memory policies. These theoretical results are supported by simulations.Comment: Submitted to 2024 American Control Conferenc