Intramural Papers of the Month (Environmental Factor, February 2022)

Intramural Papers of the Month (Environmental Factor, February 2022)

DNTP’s automated tool makes data extraction easy

A semi-automated data-extraction tool called Dextr has great potential to enhance the speed and accuracy of conducting literature reviews, according to researchers from the NIEHS Division of the National Toxicology Program.

Data extraction is a time- and resource-intensive step in the analysis of scientific literature. Machine-learning methods for automating this process have been explored to address this challenge. Previous approaches have had limited utility, particularly in the field of environmental health sciences.

To address this need, the researchers developed a data-extraction tool that combines machine-learning models with an effective user interface to enable oversight and user verification. This powerful, flexible, web-based approach supports sophisticated features and capabilities when applied to scientific articles. Unlike other workflows, it supports extraction of complex concepts such as multiple experiments, exposures, or doses, allowing users to connect elements within a study.

Dextr performed as well as, or better than, manual extraction of environmental health animal studies. The tool reduced the time required for data extraction by 47% and achieved similar precision and recall for entities such as species, strain, and sex. According to the researchers, Dextr can reduce the workload and resources required for systematic literature reviews in various fields without compromising necessary rigor and transparency. (JW)

CitationWalker VR, Schmitt CP, Wolfe MS, Nowak AJ, Kulesza K, Williams AR, Shin R, Cohen J, Burch D, Stout MD, Shipkowski KA, Rooney AA. 2022. Evaluation of a semi-automated data extraction tool for public health literature-based reviews: Dextr. Environ Int 159:107025.

How two proteins team up to restock reproductive stem cells

Visualizing the interaction between two proteins called LST-1 and FBF-2 has shed new light on how this essential partnership regulates the self-renewal of reproductive stem cells, according to NIEHS researchers and their collaborators.

In roundworms, FBF-2 binds to specific RNA sequences to promote self-renewal of germline stem cells (GSCs). This process perpetuates the pool of cells that give rise to egg and sperm cells and that are responsible for the transgenerational flow of genetic information. The functions of FBF-2 hinge on physical interactions with other proteins, including LST-1. Misexpression of both FBF-2 and LST-1 can drive the formation of reproductive cell tumors, and LST-1 mutations can cause infertility.

The researchers examined how LST-1 may regulate the activity of FBF-2 by analyzing crystal structures of RNA-protein complexes. They discovered key differences in contacts between FBF-2 and specific amino acids in peptide regions called LST-1 A and LST-1 B. In particular, LST-1 B, but not LST-1 A, modulates the RNA-binding affinity of FBF-2. The findings demonstrate that the two FBF interaction sites in LST-1 harbor important functional differences. (JW)

CitationQiu C, Wine RN, Campbell ZT, Hall TMT. 2022. Bipartite interaction sites differentially modulate RNA-binding affinity of a protein complex essential for germline stem cell self-renewal. Nucleic Acids Res 50(1):536–548.

Sister Study reveals new vitamin D, breast cancer association

Women living in areas of higher exposure to ultraviolet (UV) radiation had a lower risk of developing a particular type of breast cancer, according to research by NIEHS scientists who analyzed data from the Sister Study. UV exposure increases the risk of skin cancer, but UV radiation is also a source of vitamin D, which is thought to have protective properties against breast cancer.

Researchers analyzed the relationship between residential UV exposure and breast cancer risk, considering whether the tumor was estrogen receptor (ER) negative (ER-) or ER-positive (ER+). The study participants completed detailed questionnaires, including on their vitamin D supplement use.

Findings suggest that women who lived in the highest category of UV exposure during adulthood, compared with the lowest category, had on average a 27% lower risk of developing ER- breast cancer. This inverse association was only evident among women who did not report regularly taking vitamin D-containing supplements. No association was observed for living in areas with higher levels of UV radiation and overall breast cancer risk, nor with the development of ER+ breast cancer. The findings suggest a role of vitamin D in the development of ER- breast cancer, which has few established risk factors and tends to be a more aggressive tumor. (JH)

CitationGregoire AM, VoPham T, Laden F, Yarosh R, O’Brien KM, Sandler DP, White AJ. 2022. Residential ultraviolet radiation and breast cancer risk in a large prospective cohort. Environ Int 159:107028.

New method detects early Parkinson’s Disease in animal models

Researchers at NIEHS have developed a new method to detect the loss of dopamine-producing neurons (DANs) in part of the brain associated with motor control. The technique is called the Dopamine Neuron Challenge Test (DNC Test), and it identifies loss of DANs, an identifying pathological feature of Parkinson’s Disease (PD). Unfortunately, the hallmark symptoms of PD do not manifest until more than 60% of DANs are gone, so earlier diagnosis of the disease can allow for interventions to slow progression or even halt PD in its earliest stages.

The DNC Test uses United States. Food and Drug Administration–approved drugs known to modulate dopamine, a crucial neurotransmitter. In two PD mouse models, simultaneously administering methylphenidate and haloperidol stimulated the brain to release dopamine. Then, the scientists measured dopamine metabolites in the cerebrospinal fluid and plasma of the mice using high-performance liquid chromatography. The drug challenge revealed differences otherwise undetectable in a resting state.

If successfully translated for use as a diagnostic test for humans, the DNC Test can enable physicians to discover the loss of DANs at less than 30% instead of 60%, potentially improving length and quality of life for people with PD. (KC)

CitationZhou J, Li J, Papaneri AB, Kobzar NP, Cui G. 2021. Dopamine Neuron Challenge Test for early detection of Parkinson’s disease. NPJ Parkinsons Dis 7(1):116.

Polymerase delta proofreading ensures fidelity during DNA replication

By investigating DNA replication processes in the yeast Saccharomyces cerevisiae, NIEHS scientists have demonstrated how nucleotide selectivity, proofreading, and mismatch repair (MMR) cooperate to achieve symmetrical error rates between the leading and lagging strands in an intrinsically asymmetrical process. The work provides some insight into the origins and signatures of mutations in cancers with polymerase defects.

During replication, the correct nucleotides are selectively incorporated by polymerases (Pol) alpha, delta, and epsilon. Pols delta and epsilon also possess exonucleolytic activities capable of proofreading wrongly incorporated nucleotides. This study demonstrated that Pol delta not only proofreads errors in cis, or intrinsic proofreading, but also proofreads errors made by Pol delta and epsilon in trans, or extrinsic proofreading.

A series of yeast strains were used to conduct mutation accumulation experiments across the genome, with some modified to contain mutations that abolish proofreading and MMR. This study showed that replication error rates were balanced between the two strands. MMR was more efficient on the lagging strands. This imbalance was countered by the more efficient proofreading on the leading strands conferred by both intrinsic proofreading by Pol epsilon and extrinsic proofreading by Pol delta. The research highlighted the previously underappreciated processes of extrinsic proofreading. (KC)

CitationZhou ZX, Lujan SA, Burkholder AB, St Charles J, Dahl J, Farrell CE, Williams JS, Kunkel TA. 2021. How asymmetric DNA replication achieves symmetrical fidelity. Nat Struct Mol Biol 28(12):1020–1028.

(Kelley Christensen is a contract writer and editor for the NIEHS Office of Communications and Public Liaison [OCPL]. Jennifer Harker, Ph.D., is a technical writer-editor for OCPL. Janelle Weaver, Ph.D., is a contract writer for OCPL.)

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