Pharmacogenomic Biomarkers and Their Applications in Psychiatry.

Realizing the promise of precision medicine in psychiatry is a laudable and beneficial endeavor, since it should markedly reduce morbidity and mortality and, in effect, alleviate the economic and social burden of psychiatric disorders. This review aims to summarize important issues on pharmacogenomics in psychiatry that have laid the foundation towards personalized pharmacotherapy and, in a broader sense, precision medicine. We present major pharmacogenomic biomarkers and their applications in a variety of psychiatric disorders, such as depression, attention-deficit/hyperactivity disorder (ADHD), narcolepsy, schizophrenia, and bipolar disorder. In addition, we extend the scope into epilepsy, since antiepileptic drugs are widely used to treat psychiatric disorders, although epilepsy is conventionally considered to be a neurological disorder.

RNA-binding as chaperones of DNA binding proteins from starved cells.

DNA-binding proteins from starved cells (Dps) in Escherichia coli protects DNA from multiple stresses during the stationary phase by forming a stable Dps-DNA complex. In contrast, Dps cannot bind to DNA during the exponential phase and it has not been clear why Dps conditionally binds to DNA depending on the growth phase. In this study, we show that DNA-free Dps in the exponential phase can also bind to RNA and the preemptive binding of RNA precludes DNA from interacting with Dps. The critical role of RNA in modulating the stability and functional competence of Dps and their morphology, leads us to propose a two-state model of Dps in executing stress responses. In the exponential phase, Dps is present predominantly as ribonucleoprotein complex. Under starvation, RNAs are degraded by up-regulated RNases, activating Dps to bind with chromosomal DNAs protecting them from diverse stresses. A dual role of RNA as an inhibitor of DNA binding and chaperone to keep dynamic functional status of Dps would be crucial for operating an immediate protection of chromosomal DNAs on starvation. The holdase-type chaperoning role of RNA in Dps-mediated stress responses would shed light on the role of RNAs as chaperone (Chaperna).

Publisher Correction: Conversion of a soluble protein into a potent chaperone in vivo.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Conversion of a soluble protein into a potent chaperone in vivo.

Molecular chaperones play an important role in cellular protein-folding assistance and aggregation inhibition. As a different but complementary model, we previously proposed that, in general, soluble cellular macromolecules with large excluded volume and surface charges exhibit intrinsic chaperone activity to prevent aggregation of their connected polypeptides irrespective of the connection type, thereby contributing to efficient protein folding. As a proof of concept, we here demonstrated that a model recombinant protein with a specific sequence-binding domain robustly exerted chaperone activity toward various proteins harbouring a short recognition tag of 7 residues in Escherichia coli. The chaperone activity of this protein was comparable to that of representative E. coli chaperones in vivo. Furthermore, in vitro refolding experiments confirmed the in vivo results. Our findings reveal that a soluble protein exhibits the intrinsic chaperone activity to prevent off-pathway aggregation of its interacting proteins, leading to more productive folding while allowing them to fold according to their intrinsic folding pathways. This study gives new insights into the plausible chaperoning role of soluble cellular macromolecules in terms of aggregation inhibition and indirect folding assistance.

Correction: Awareness and attitude of the public toward personalized medicine in Korea.

[This corrects the article DOI: 10.1371/journal.pone.0192856.].

Awareness and attitude of the public toward personalized medicine in Korea.

OBJECTIVES: As personalized medicine (PM) is expected to greatly improve health outcomes, efforts have recently been made for its clinical implementation in Korea. We aimed to evaluate public awareness and attitude regarding PM. METHODS: We performed a self-administered questionnaire survey to 703 adults, who participated in the survey on a voluntary basis. The primary outcome measures included public knowledge, attitude, and acceptance of PM. We conducted multinomial multivariate logistic analysis for outcome variables with three response categories and performed multivariate logistic regression analyses for dichotomous outcome variables. RESULTS: Only 28% of participants had knowledge that genetic factors can contribute to inter-individual variations in drug response and the definition of PM (199 out of 702). Higher family income was correlated with greater knowledge concerning PM (OR = 3.76, p = 0.034). A majority of respondents preferred integrated pharmacogenomic testing over drug-specific testing and agreed to inclusion of pharmacogenomic testing in the national health examination (64% and 77%, respectively), but only 51% were willing to pay for it. DISCUSSION: Our results identify the urgent need for public education as well as the potential health disparities in access to PM. This study helps to frame policies for implementing PM in clinical practice.

Exploiting virus-like particles as innovative vaccines against emerging viral infections.

Emerging viruses pose a major threat to humans and livestock with global public health and economic burdens. Vaccination remains an effective tool to reduce this threat, and yet, the conventional cell culture often fails to produce sufficient vaccine dose. As an alternative to cell-culture based vaccine, virus-like particles (VLPs) are considered as a highpriority vaccine strategy against emerging viruses. VLPs represent highly ordered repetitive structures via macromolecular assemblies of viral proteins. The particulate nature allows efficient uptake into antigen presenting cells stimulating both innate and adaptive immune responses towards enhanced vaccine efficacy. Increasing research activity and translation opportunity necessitate the advances in the design of VLPs and new bioprocessing modalities for efficient and cost-effective production. Herein, we describe major achievements and challenges in this endeavor, with respect to designing strategies to harnessing the immunogenic potential, production platforms, downstream processes, and some exemplary cases in developing VLP-based vaccines.

Combined effects of hepatocyte nuclear factor 4α and constitutive androstane receptor on stable warfarin doses.

A possible association between the combination of genetic variations in hepatocyte nuclear factor 4α (HNF4α) and constitutive androstane receptor (CAR) and the stable doses of warfarin was examined in patients from the Ewha-Severance Treatment (EAST) Group of Warfarin. Around 42.5% of the overall interindividual variability in warfarin dose requirements was explained by the multivariate regression model; the vitamin K epoxide reductase complex 1 (VKORC1) genotype accounted for 29.6%, the cytochrome P450 (CYP) 2C9 genotype for 4.3%, age for 3.6%, the CYP4F2 genotype for 3.3%, and CAR/HNF4α (rs2501873/rs3212198) for 1.7%. Our results showed that the combination of CAR and HNF4α genotypes could be determinants of stable warfarin doses.

Protein folding in vivo revisited.

Protein folding in vivo is extremely intricate and challenging to examine or predict because the conformational changes, including folding, misfolding, and aggregation, are largely influenced by the cellular environment. Traditionally, cellular protein folding has been considered predominantly in the context of the Anfinsen postulate and molecular chaperones. However, accumulating evidence reveals that these models have limitations. In this review we revisit these models, and discuss co-translational folding, binding partner-mediated folding, and RNA-mediated folding as alternative or supplementary folding helpers. In addition, we discuss the folding helper systems mediated by macromolecules (e.g., ribosomes, membranes, and prefolded domains in multidomain proteins) that are tightly linked to newly synthesized polypeptides during protein biogenesis. These cis-acting folding helper systems, conceptually different from the trans-acting molecular chaperones, could play a crucial role in protein folding in vivo. Importantly, there is increasing evidence that the surface charges and excluded volume of macromolecules are important factors for stabilizing their connected polypeptides against aggregation. This stabilizing mechanism suggests that macromolecules including RNAs and proteins, let alone molecular chaperones, have an intrinsic ability to exert chaperoning function on their connected polypeptides independent of the linkage type between them. As an effective way to overcome the adverse effect of macromolecular crowding on protein folding, here we suggest that nascent polypeptide chains utilize the crowded environment in favor of productive folding by interacting with macromolecules.

Macromolecule-assisted de novo protein folding.

In the processes of protein synthesis and folding, newly synthesized polypeptides are tightly connected to the macromolecules, such as ribosomes, lipid bilayers, or cotranslationally folded domains in multidomain proteins, representing a hallmark of de novo protein folding environments in vivo. Such linkage effects on the aggregation of endogenous polypeptides have been largely neglected, although all these macromolecules have been known to effectively and robustly solubilize their linked heterologous proteins in fusion or display technology. Thus, their roles in the aggregation of linked endogenous polypeptides need to be elucidated and incorporated into the mechanisms of de novo protein folding in vivo. In the classic hydrophobic interaction-based stabilizing mechanism underlying the molecular chaperone-assisted protein folding, it has been assumed that the macromolecules connected through a simple linkage without hydrophobic interactions and conformational changes would make no effect on the aggregation of their linked polypeptide chains. However, an increasing line of evidence indicates that the intrinsic properties of soluble macromolecules, especially their surface charges and excluded volume, could be important and universal factors for stabilizing their linked polypeptides against aggregation. Taken together, these macromolecules could act as folding helpers by keeping their linked nascent chains in a folding-competent state. The folding assistance provided by these macromolecules in the linkage context would give new insights into de novo protein folding inside the cell.

Identification of mutations that alter the gating of the Escherichia coli mechanosensitive channel protein, MscK.

Mechanosensitive channels allow bacteria to survive rapid increases in turgor pressure. Substantial questions remain as to how these channels sense and respond to mechanical stress. Here we describe a set of mutants with alterations in their MscK channel protein. The mutants were detected fortuitously by their enhanced ability to modify the accumulation of quinolinic acid. Some amino acid changes lie in the putative pore region of MscK, but others affect sequences that lie amino-terminal to the domain aligning with MscS. We demonstrate that the alterations in MscK cause the channel to open more frequently in the absence of excessive mechanical stress. This is manifested in changes in sensitivity to external K(+) by cells expressing the mutant proteins. Single-channel analysis highlighted a range of gating behaviours: activation at lower pressures than the wild type, inability to achieve the fully open state or a modified requirement for K(+). Thus, the dominant uptake phenotype of these mutants may result from a defect in their ability to regulate the gating of MscK. The locations of the substituted residues suggest that the overall gating mechanism of MscK is comparable to that of MscS, but with subtleties introduced by the additional protein sequences in MscK.

Function-altering SNPs in the human multidrug transporter gene ABCB1 identified using a Saccharomyces-based assay.

The human ABCB1 (MDR1)-encoded multidrug transporter P-glycoprotein (P-gp) plays a major role in disposition and efficacy of a broad range of drugs including anticancer agents. ABCB1 polymorphisms could therefore determine interindividual variability in resistance to these drugs. To test this hypothesis we developed a Saccharomyces-based assay for evaluating the functional significance of ABCB1 polymorphisms. The P-gp reference and nine variants carrying amino-acid-altering single nucleotide polymorphisms (SNPs) were tested on medium containing daunorubicin, doxorubicin, valinomycin, or actinomycin D, revealing SNPs that increased (M89T, L662R, R669C, and S1141T) or decreased (W1108R) drug resistance. The R669C allele's highly elevated resistance was compromised when in combination with W1108R. Protein level or subcellular location of each variant did not account for the observed phenotypes. The relative resistance profile of the variants differed with drug substrates. This study established a robust new methodology for identification of function-altering polymorphisms in human multidrug transporter genes, identified polymorphisms affecting P-gp function, and provided a step toward genotype-determined dosing of chemotherapeutics.