Functional Polymorphism of the Mu-Opioid Receptor Gene (OPRM1) Influences Reinforcement Learning in Humans

Previous reports on the functional effects (i.e., gain or loss of function), and phenotypic outcomes (e.g., changes in addiction vulnerability and stress response) of a commonly occurring functional single nucleotide polymorphism (SNP) of the mu-opioid receptor (OPRM1 A118G) have been inconsistent. Here we examine the effect of this polymorphism on implicit reward learning. We used a probabilistic signal detection task to determine whether this polymorphism impacts response bias to monetary reward in 63 healthy adult subjects: 51 AA homozygotes and 12 G allele carriers. OPRM1 AA homozygotes exhibited typical responding to the rewarded response—that is, their bias to the rewarded stimulus increased over time. However, OPRM1 G allele carriers exhibited a decline in response to the rewarded stimulus compared to the AA homozygotes. These results extend previous reports on the heritability of performance on this task by implicating a specific polymorphism. Through comparison with other studies using this task, we suggest a possible mechanism by which the OPRM1 polymorphism may confer reduced response to natural reward through a dopamine-mediated decrease during positive reinforcement learning

Evofosfamide for the Treatment of Human Papillomavirus-Negative Head and Neck Squamous Cell Carcinoma

Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line–derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication

Responses of respiration in the light to warming in field-grown trees : a comparison of the thermal sensitivity of the Kok and Laisk methods

The Kok and Laisk techniques can both be used to estimate light respiration R-light. We investigated whether responses of R-light to short- and long-term changes in leaf temperature depend on the technique used to estimate R-light. We grew Eucalyptus tereticornis in whole-tree chambers under ambient temperature (AT) or AT + 3 degrees C (elevated temperature, ET). We assessed dark respiration R-dark and light respiration with the Kok (R-Kok) and Laisk (R-Laisk) methods at four temperatures to determine the degree of light suppression of respiration using both methods in AT and ET trees. The ET treatment had little impact on R-dark, R-Kok or R-Laisk. Although the thermal sensitivities of R-Kok or R-Laisk were similar, R-Kok was higher than R-Laisk. We found negative values of R-Laisk at the lowest measurement temperatures, indicating positive net CO2 uptake, which we propose may be related to phosphoenolpyruvate carboxylase activity. Light suppression of R-dark decreased with increasing leaf temperature, but the degree of suppression depended on the method used. The Kok and Laisk methods do not generate the same estimates of R-light or light suppression of R-dark between 20 and 35 degrees C. Negative rates of R-Laisk imply that this method may become less reliable at low temperatures

Responses of respiration in the light to warming in field-grown trees : a comparison of the thermal sensitivity of the Kok and Laisk methods

The Kok and Laisk techniques can both be used to estimate light respiration R light . We investigated whether responses of R light to short- and long-term changes in leaf temperature depend on the technique used to estimate R light. We grew Eucalyptus tereticornis in whole-tree chambers under ambient temperature (AT) or AT + 3 ° C (elevated temperature, ET). We assessed dark respiration R dark and light respiration with the Kok ( R Kok ) and Laisk ( R Laisk ) methods at four temperatures to determine the degree of light suppression of respiration using both methods in AT and ET trees. The ET treatment had little impact on R dark , R Kok or R Laisk. Although the thermal sensitivities of R Kok or R Laisk were similar, R Kok was higher than R Laisk. We found negative values of R Laisk at the lowest measurement temperatures, indicating positive net CO 2 uptake, which we pro- pose may be related to phosphoenolpyruvate carboxylase activity. Light suppression of R dark decreased with increasing leaf temperature, but the degree of suppression depended on the method used. The Kok and Laisk methods do not generate the same estimates of R light or light suppression of R dark between 20 and 35 ° C. Negative rates of R Laisk imply that this method may become less reliable at low temperatures

Responses of respiration in the light to warming in field‐grown trees: a comparison of the thermal sensitivity of the Kok and Laisk methods

The Kok and Laisk techniques can both be used to estimate light respiration R light . We investigated whether responses of R light to short- and long-term changes in leaf temperature depend on the technique used to estimate R light. We grew Eucalyptus tereticornis in whole-tree chambers under ambient temperature (AT) or AT + 3 ° C (elevated temperature, ET). We assessed dark respiration R dark and light respiration with the Kok ( R Kok ) and Laisk ( R Laisk ) methods at four temperatures to determine the degree of light suppression of respiration using both methods in AT and ET trees. The ET treatment had little impact on R dark , R Kok or R Laisk. Although the thermal sensitivities of R Kok or R Laisk were similar, R Kok was higher than R Laisk. We found negative values of R Laisk at the lowest measurement temperatures, indicating positive net CO 2 uptake, which we pro- pose may be related to phosphoenolpyruvate carboxylase activity. Light suppression of R dark decreased with increasing leaf temperature, but the degree of suppression depended on the method used. The Kok and Laisk methods do not generate the same estimates of R light or light suppression of R dark between 20 and 35 ° C. Negative rates of R Laisk imply that this method may become less reliable at low temperatures

The perceptions and experiences of women who achieved and did not achieve a waterbirth

There is a gap in knowledge and understanding relating to the experiences of women exposed to the opportunity of waterbirth. Our aim was to explore the perceptions and experiences of women who achieved or did not achieve their planned waterbirth