During the last three decades, the impact of chemical pollution has focused almost exclusively on the conventional "priority" pollutants, especially those acutely toxic/carcinogenic pesticides and industrial intermediates displaying persistence in the environment. This spectrum of chemicals, however, is only one piece of the larger puzzle in "holistic" risk assessment. Another diverse group of bioactive chemicals receiving comparatively little attention as potential environmental pollutants includes the pharmaceuticals and active ingredients in personal care products (in this review collectively termed PPCPs), both human and veterinary, including not just prescription drugs and biologics, but also diagnostic agents, "nutraceuticals," fragrances, sun-screen agents, and numerous others. These compounds and their bioactive metabolites can be continually introduced to the aquatic environment as complex mixtures via a number of routes but primarily by both untreated and treated sewage. Aquatic pollution is particularly troublesome because aquatic organisms are captive to continual life-cycle, multigenerational exposure. The possibility for continual but undetectable or unnoticed effects on aquatic organisms is particularly worrisome because effects could accumulate so slowly that major change goes undetected until the cumulative level of these effects finally cascades to irreversible change--change that would otherwise be attributed to natural adaptation or ecologic succession. As opposed to the conventional, persistent priority pollutants, PPCPs need not be persistent if they are continually introduced to surface waters, even at low parts-per-trillion/parts-per-billion concentrations (ng-microg/L). Even though some PPCPs are extremely persistent and introduced to the environment in very high quantities and perhaps have already gained ubiquity worldwide, others could act as if they were persistent, simply because their continual infusion into the aquatic environment serves to sustain perpetual life-cycle exposures for aquatic organisms. This review attempts to synthesize the literature on environmental origin, distribution/occurrence, and effects and to catalyze a more focused discussion in the environmental science community.

Pharmaceuticals and personal care products in the environment: agents of subtle change?

Long-term potentiation of synaptic transmission in the hippocampus is the leading experimental model for the synaptic changes that may underlie learning and memory. This review presents a current understanding of the molecular mechanisms of this long-lasting increase in synaptic strength and describes a simple model that unifies much of the data that previously were viewed as contradictory.

/pdf/long-term-potentiation-a-decade-of-progress-1y4lo4uwwe.pdf

Long-Term Potentiation--A Decade of Progress?

The N-methyl d-aspartate (NMDA) receptor subtype of glutamate-gated ion channels possesses high calcium permeability and unique voltage-dependent sensitivity to magnesium and is modulated by glycine Molecular cloning identified three complementary DNA species of rat brain, encoding NMDA receptor subunits NMDAR2A (NR2A), NR2B, and NR2C, which are 55 to 70% ientical in sequence These are structurally related, with less than 20% sequence identity, to other excitatory amino acid receptor subunits, including the NMDA receptor subunit NMDAR1 (NR1) Upon expression in cultured cells, the new subunits yielded prominent, typical glutamate-and NMDA-activated currents only when they were in heteromeric configurations with NR1 NR1-NR2A and NR1-NR2C channels differed in gating behavior and magnesium sensitivity Such heteromeric NMDA receptor subtypes may exist in neurons, since NR1 messenger RNA is synthesized throughout the mature rat brain, while NR2 messenger RNA show a differential distribution

https://science.sciencemag.org/content/sci/256/5060/1217.full.pdf

Heteromeric NMDA receptors: Molecular and functional distinction of subtypes

Signaling--2000 and beyond.

Long-term potentiation (LTP) in the CA1 region of the hippocampus has been the primary model by which to study the cellular and molecular basis of memory. Calcium/calmodulin-dependent protein kinase II (CaMKII) is necessary for LTP induction, is persistently activated by stimuli that elicit LTP, and can, by itself, enhance the efficacy of synaptic transmission. The analysis of CaMKII autophosphorylation and dephosphorylation indicates that this kinase could serve as a molecular switch that is capable of long-term memory storage. Consistent with such a role, mutations that prevent persistent activation of CaMKII block LTP, experience-dependent plasticity and behavioural memory. These results make CaMKII a leading candidate in the search for the molecular basis of memory.

The molecular basis of CaMKII function in synaptic and behavioural memory.

Regulation of brain Type II Ca2+ calmodulin - dependent protein kinase by autophosphorylation: A Ca2+-triggered molecular switch

Distinct forebrain and cerebellar isozymes of type II Ca2+/calmodulin-dependent protein kinase associate differently with the postsynaptic density fraction.

Sequences of autophosphorylation sites in neuronal type II CaM kinase that control Ca2(+)-independent activity.

Eltrombopag is a first-in-class, orally bioavailable, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies In vitro studies have demonstrated that the activity of eltrombopag is dependent on expression of TpoR, which activates the signaling transducers and activators of transcription (STAT) and mitogen-activated protein kinase signal transduction pathways The objective of this preclinical study is to determine if eltrombopag interacts selectively with the TpoR to facilitate megakaryocyte differentiation in platelets Functional thrombopoietic activity was demonstrated by the proliferation and differentiation of primary human CD34(+) bone marrow cells into CD41(+) megakaryocytes Measurements in platelets in several species indicated that eltrombopag specifically activates only the human and chimpanzee STAT pathways The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg per day for 5 days) to chimpanzees In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production These results suggest that eltrombopag and Tpo may be able to act additively to increase platelet production

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1634/stemcells.2008-0366

Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist.

https://www.exphem.org/article/S0301-472X(04)00320-0/pdf

Stephen G. Miller

Papers

Regulation of brain Type II Ca2+ calmodulin - dependent protein kinase by autophosphorylation: A Ca2+-triggered molecular switch

Distinct forebrain and cerebellar isozymes of type II Ca2+/calmodulin-dependent protein kinase associate differently with the postsynaptic density fraction.

Sequences of autophosphorylation sites in neuronal type II CaM kinase that control Ca2(+)-independent activity.

Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist.

Discovery and characterization of a selective, nonpeptidyl thrombopoietin receptor agonist.