Biosynthesis, Engineering, and Delivery of Selenoproteins.

Selenocysteine (Sec) was discovered as the 21st genetically encoded amino acid. In nature, site-directed incorporation of Sec into proteins requires specialized biosynthesis and recoding machinery that evolved distinctly in bacteria compared to archaea and eukaryotes. Many organisms, including higher plants and most fungi, lack the Sec-decoding trait.

Delivery of the selenoprotein thioredoxin reductase 1 to mammalian cells.

Over-expression of genetically encoded thioredoxin reductase 1 (TrxR1) TrxR1 can be toxic to cells due to the formation of a truncated version of the enzyme. We developed a new mammalian cell-based model to investigate TrxR1 activity. Fusion of the HIV-derived cell penetrating peptide (TAT) enabled efficient cellular uptake of purified TrxR1 containing 21 genetically encoded amino acids, including selenocysteine.

A novel fluorescent reporter sensitive to serine mis-incorporation.

High-fidelity translation was considered a requirement for living cells. The frozen accident theory suggested that any deviation from the standard genetic code should result in the production of so much mis-made and non-functional proteins that cells cannot remain viable. Studies in bacterial, yeast, and mammalian cells show that significant levels of mistranslation (1-10% per codon) can be tolerated or even beneficial under conditions of oxidative stress.

Acetylated Thioredoxin Reductase 1 Resists Oxidative Inactivation.

Thioredoxin Reductase 1 (TrxR1) is an enzyme that protects human cells against reactive oxygen species generated during oxidative stress or in response to chemotherapies. Acetylation of TrxR1 is associated with oxidative stress, but the function of TrxR1 acetylation in oxidizing conditions is unknown. Using genetic code expansion, we produced recombinant and site-specifically acetylated variants of TrxR1 that also contain the non-canonical amino acid, selenocysteine, which is essential for TrxR1 activity.

Expanded FDA regulation of health and wellness apps.

This paper argues that the Food and Drug Administration's (FDA) policy for health and wellness apps is ethically problematic. Currently, the FDA does not regulate health and wellness apps that are not intended for medical use. As a result of this hands-off policy, preventing harm to consumers is left primarily to developers and app marketplaces.

The Molecular Architecture of Unnatural Amino Acid Translation Systems.

Expanding the genetic code using non-canonical amino acids has revolutionized synthetic biology. In a recent issue of Cell Chemical Biology, Yanagisawa et al. (2019) expanded our knowledge of orthogonal translation systems by presenting a tour de force structural characterization of multiple genetic code expansion systems based on pyrrolysyl-tRNA synthetase.

Acetylation Regulates Thioredoxin Reductase Oligomerization and Activity.

Aims: Thioredoxin reductase 1 (TrxR1) is a cancer target and essential selenoprotein that defends the cell against reactive oxygen species and regulates cellular signaling and redox pathways. Previous cell-based studies correlated TrxR1 acetylation with modulated cellular reduction activity, yet the function of specific acetylation sites on TrxR1 remains unknown.

Innovation: We produced site-specifically acetylated TrxR1 variants that also contain selenocysteine (Sec).

A systematic review of biomarkers for disease progression in Alzheimer's disease.

Background: Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true slowing of the neurodegenerative process. A systematic review was undertaken to determine what biomarkers for disease progression in Alzheimer's disease exist and how well they perform.

Methods: MEDLINE and Embase (1950-2011) were searched using five search strategies.

The emergence of the Responsible Conduct of Research (RCR) in PHS policy and practice.

The Responsible Conduct of Research (RCR) is now an established academic field taught at virtually every major American research university and generates a growing volume of research and pedagogical literature. Paradoxically, it is a field without a consensually agreed upon definition, goals, foundational theories, research agenda, and pedagogical methodology. It has been suggested that RCR as currently being taught is ineffective in preventing misconduct and improving the quality of research.

A systematic review of biomarkers for disease progression in Parkinson's disease.

Background: Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true disease-modifying effects. A systematic review was undertaken to determine what biomarkers for disease progression in Parkinson's disease (PD) exist.

Methods: MEDLINE and EMBASE (1950-2010) were searched using five search strategies.

Preparing whistleblowers for reporting research misconduct.

Making an allegation of research misconduct can be stressful for a whistleblower. The Research Integrity Officer (RIO) can play an important role in helping reduce the stress by thoroughly discussing what whistleblowers can expect if they make an allegation. Through interviews with 77 RIOs who had recently handled a research misconduct case, we found that RIOs who addressed more topics as well as specific aspects of the topics were more likely to have used some type of memory aide in their initial contact with whistleblowers, talked with ORI staff or other RIOs about "hypothetical" research misconduct cases, or attended a RIO boot camp training.

Assessing the preparedness of research integrity officers (RIOs) to appropriately handle possible research misconduct cases.

Institutions receiving federal funding for research from the U.S.Public Health Service need to have policies and procedures to both prevent research misconduct and to adjudicate it when it occurs.

Mentoring and research misconduct: an analysis of research mentoring in closed ORI cases.

We are reporting on how involved the mentor was in promoting responsible research in cases of research misconduct. We reviewed the USPHS misconduct files of the Office of Research Integrity. These files are created by Institutions who prosecute a case of possible research misconduct; ORI has oversight review of these investigations.

Assessing newborn body composition using principal components analysis: differences in the determinants of fat and skeletal size.

Background: Birth weight is a composite of skeletal size and soft tissue. These components are likely to have different growth patterns. The aim of this paper is to investigate the association between established determinants of birth weight and these separate components.

Repeated measurement of pregnancy-associated plasma protein-A (PAPP-A) in Down syndrome screening: a validation study.

Objectives: To confirm that measuring pregnancy-associated plasma protein-A (PAPP-A) in both first- and second-trimester serum samples improves Down syndrome screening.

Methods: We selected paired first- and second-trimester stored serum samples from 34 Down syndrome pregnancies (cases) and 514 unaffected pregnancies (controls) and tested the second-trimester samples for PAPP-A and dimeric inhibin-A (DIA). First-trimester PAPP-A measurements were already available, as were second-trimester measurements of alpha-fetoprotein, unconjugated estriol (uE3), and human chorionic gonadotrophin (hCG).

Repeated measures screening for Down's Syndrome.

Objective: To demonstrate the potential value of screening for Down's Syndrome using highly correlated repeated measures of serum markers taken in the first and second trimesters of pregnancy.

Design: A Monte Carlo simulation study.

Population: Detection rates and false positive rates relating to the maternal age distribution of England and Wales for the period 1996 to 1998 were obtained using marker distributions from the SURUSS study.