Dyrk1a is required for craniofacial development in Xenopus laevis.

Loss of function variations in the dual specificity tyrosine-phosphorylation-regulated kinase 1 A (DYRK1A) gene are associated with craniofacial malformations in humans. Here we characterized the effects of deficient DYRK1A in craniofacial development using a developmental model, Xenopus laevis. Dyrk1a mRNA and protein were expressed throughout the developing head and both were enriched in the branchial arches which contribute to the face and jaw. Consistently, reduced Dyrk1a function, using dyrk1a morpholinos and pharmacological inhibitors, resulted in orofacial malformations including hypotelorism, altered mouth shape, slanted eyes, and narrower face accompanied by smaller jaw cartilage and muscle. Inhibition of Dyrk1a function resulted in misexpression of key craniofacial regulators including transcription factors and members of the retinoic acid signaling pathway. Two such regulators, sox9 and pax3 are required for neural crest development and their decreased expression corresponds with smaller neural crest domains within the branchial arches. Finally, we determined that the smaller size of the faces, jaw elements and neural crest domains in embryos deficient in Dyrk1a could be explained by increased cell death and decreased proliferation. This study is the first to provide insight into why craniofacial birth defects might arise in humans with variants of DYRK1A.

Prior Spontaneous or Induced Abortion Is a Risk Factor for Cervical Dysfunction in Pregnant Women: a Systematic Review and Meta-analysis.

A history of abortion is associated with cervical dysfunction during pregnancy, but there remains uncertainty about whether risk can be stratified by the abortion type, the abortion procedure, or number of previous abortions. The objective of this study was to verify the relationship between cervical dysfunction measures in pregnancies with and without a history of termination. Embase and Medline databases were searched from 01 January 1960 to 01 March 2022 resulting in a full-text review of 28 studies. The Newcastle-Ottawa Scale (NOS) was used to assess the quality and risk of bias for non-randomized studies. The meta-analysis consisted of 6 studies that met all inclusion and exclusion criteria and included a combined total of 2,513,044 pregnancies. Cervical dysfunction was defined as either cervical insufficiency/incompetence in 4 of the studies and as short cervix in the others. Results from a random-effects model using reported adjusted odds ratios (aOR) estimated an increase in the odds of 2.71 (95% CI 1.76, 4.16) for cervical dysfunction in the current pregnancy related to a history of induced or spontaneous abortion. Subgroup analyses with only induced abortions (surgical/medical) estimated an aOR of 2.54 (95% CI 1.41, 4.57), while studies limited to surgical abortions had an aOR of 4.08 (95% CI 2.84, 5.86). The risk of cervical dysfunction in the current pregnancy was also found to be dependent on the number of previous abortions. In this meta-analysis, a prior history of abortion, and specifically induced abortions, was associated with cervical dysfunction. The protocol was registered in PROSPERO (CRD42020209723).

Racial disparities in treatment-related cardiovascular toxicities amongst women with breast cancer: a scoping review.

PURPOSE: Black women often experience poorer breast cancer-related outcomes and higher mortality than white women. A contributor to this disparity may relate to the disproportionate burden of cancer treatment-related cardiovascular (CV) toxicities. The objective of this review is to identify studies that report racial differences in CV toxicity risk. METHODS: Medline and Embase were searched for studies that assessed CV toxicities as the outcome(s) and included Black and White women with breast cancer. Studies were selected based on inclusion/exclusion criteria and through the use of multiple reviewers. RESULTS: The review included 13 studies following a review of 409 citations and 49 full-text articles. All studies were retrospective and 8/13 utilized data from the Surveillance, Epidemiology, and End Results-Medicare linked database. Trastuzumab was the most frequently studied treatment. The proportion of Black women in these studies ranged from 5.5 to 63%. A majority of studies reported a higher risk of CV toxicity amongst Black women when compared to white women (93%). Black women had up to a two times higher risk of CV toxicity (HR, 2.73 (CI, 1.24 to 6.01)) compared to white women. Only one study evaluated the role of socioeconomic factors in explaining racial differences in CV toxicity; however, the disparity remained even after adjusting for these factors. CONCLUSIONS: There is a critical need for more longitudinal studies that evaluate multilevel factors (e.g., psychosocial, biological) that may help to explain this disparity. IMPLICATIONS FOR CANCER SURVIVORS: Black cancer survivors may require additional surveillance and mitigation strategies to decrease disproportionate burden of CV toxicities.

Designing a Workflow for Online Learning Objects Created by Health Sciences Librarians.

The COVID-19 lockdown led to immediate changes in how Virginia Commonwealth University's (VCU) Health Sciences Library (HSL) would support faculty and students through the means of online learning objects (OLOs). Each Research and Education (RED) librarian is responsible for responding to the educational needs of a specific health sciences school or college as well as those of the VCU Health System. A rapid increase in the OLO creation required a mechanism to curate these objects, make them available to all liaisons, and standardize workflows. The act of curating and creating standardized workflows would allow for easier management and updating of content, the ability to share and cross-pollinate content between liaisons, and the prevention of duplicated content by liaisons, thus lessening the workload. Support from key stakeholders, including RED administrators, the Online Learning Librarian (OLL), and the Multimedia Teaching and Learning Librarian (MTLL), enabled a team of RED librarians (who formed an Online Learning Team (OLT)) to standardize workflows and upload them to the department's intranet for future reference.

E-liquids and vanillin flavoring disrupts retinoic acid signaling and causes craniofacial defects in Xenopus embryos.

Environmental teratogens such as smoking are known risk factors for developmental disorders such as cleft palate. While smoking rates have declined, a new type of smoking, called vaping is on the rise. Vaping is the use of e-cigarettes to vaporize and inhale an e-liquid containing nicotine and food-like flavors. There is the potential that, like smoking, vaping could also pose a danger to the developing human. Rather than waiting for epidemiological and mammalian studies, we have turned to an aquatic developmental model, Xenopus laevis, to more quickly assess whether e-liquids contain teratogens that could lead to craniofacial malformations. Xenopus, like zebrafish, has the benefit of being a well-established developmental model and has also been effective in predicting whether a chemical could be a teratogen. We have determined that embryonic exposure to dessert flavored e-liquids can cause craniofacial abnormalities, including an orofacial cleft in Xenopus. To better understand the underlying mechanisms contributing to these defects, transcriptomic analysis of the facial tissues of embryos exposed to a representative dessert flavored e-liquid vapor extract was performed. Analysis of differentially expressed genes in these embryos revealed several genes associated with retinoic acid metabolism or the signaling pathway. Consistently, retinoic acid receptor inhibition phenocopied the craniofacial defects as those embryos exposed to the vapor extract of the e-liquid. Such malformations also correlated with a group of common differentially expressed genes, two of which are associated with midface birth defects in humans. Further, e-liquid exposure sensitized embryos to forming craniofacial malformations when they already had depressed retinoic acid signaling. Moreover, 13-cis-retinoic acid treatment could significantly reduce the e-liquid induced malformation in the midface. Such results suggest the possibility of an interaction between retinoic acid signaling and e-liquid exposure. One of the most popular and concentrated flavoring chemicals in dessert flavored e-liquids is vanillin. Xenopus embryos exposed to this chemical closely resembled embryos exposed to dessert-like e-liquids and a retinoic acid receptor antagonist. In summary, we determined that e-liquid chemicals, in particular vanillin, can cause craniofacial defects potentially by dysregulating retinoic acid signaling. This work warrants the evaluation of vanillin and other such flavoring additives in e-liquids on mammalian development.

Partnering with postdocs: a library model for supporting postdoctoral researchers and educating the academic research community.

BACKGROUND: A mutually beneficial need exists between postdoctoral scholars (postdocs) who want to grow their science communication, networking, and teaching skills and those in the general health sciences research community who want to learn more about specialized topics. Recognizing this need, interdepartmental teams at two public universities began offering postdocs a teaching opportunity at their health sciences libraries, which serve as discipline-neutral learning spaces for researchers. CASE PRESENTATION: At the University of Pittsburgh (Pitt) and Virginia Commonwealth University (VCU), postdocs are invited to submit talk proposals on "how to do something" related to the health sciences. Selected postdoc speakers conduct one-hour talks, get science communication and teaching support, have their talks uploaded to YouTube, and receive feedback from attendees. CONCLUSIONS: Postdoc participants appreciated being able to participate in this program, and attendees strongly indicated that the talks are of value. At VCU, surveys of the 25 talks from 2015-2018 showed that 91% of attendees believed they had a better understanding of the topic because of their attendance, and 85% planned to use the knowledge they gained. More than a year after their talks, several postdocs across both institutions informed the coordinators that they were subsequently contacted for advice or further discussion, with 2 postdocs stating that it helped them with job opportunities. This model can be easily adapted at other health sciences libraries to benefit their academic communities.

The mechanistic target of rapamycin pathway downregulates bone morphogenetic protein signaling to promote oligodendrocyte differentiation.

Oligodendrocyte precursor cells (OPCs) differentiate and mature into oligodendrocytes, which produce myelin in the central nervous system. Prior studies have shown that the mechanistic target of rapamycin (mTOR) is necessary for proper myelination of the mouse spinal cord and that bone morphogenetic protein (BMP) signaling inhibits oligodendrocyte differentiation, in part by promoting expression of inhibitor of DNA binding 2 (Id2). Here we provide evidence that mTOR functions specifically in the transition from early stage OPC to immature oligodendrocyte by downregulating BMP signaling during postnatal spinal cord development. When mTOR is deleted from the oligodendrocyte lineage, expression of the FK506 binding protein 1A (FKBP12), a suppressor of BMP receptor activity, is reduced, downstream Smad activity is increased and Id2 expression is elevated. Additionally, mTOR inhibition with rapamycin in differentiating OPCs alters the transcriptional complex present at the Id2 promoter. Deletion of mTOR in oligodendroglia in vivo resulted in fewer late stage OPCs and fewer newly formed oligodendrocytes in the spinal cord with no effect on OPC proliferation or cell cycle exit. Finally, we demonstrate that inhibiting BMP signaling rescues the rapamycin-induced deficit in myelin protein expression. We conclude that mTOR promotes early oligodendrocyte differentiation by suppressing BMP signaling in OPCs.

Transcriptome analysis of Xenopus orofacial tissues deficient in retinoic acid receptor function.

BACKGROUND: Development of the face and mouth is orchestrated by a large number of transcription factors, signaling pathways and epigenetic regulators. While we know many of these regulators, our understanding of how they interact with each other and implement changes in gene expression during orofacial development is still in its infancy. Therefore, this study focuses on uncovering potential cooperation between transcriptional regulators and one important signaling pathway, retinoic acid, during development of the midface. RESULTS: Transcriptome analyses was performed on facial tissues deficient for retinoic acid receptor function at two time points in development; early (35 hpf) just after the neural crest migrates and facial tissues are specified and later (60 hpf) when the mouth has formed and facial structures begin to differentiate. Functional and network analyses revealed that retinoic acid signaling could cooperate with novel epigenetic factors and calcium-NFAT signaling during early orofacial development. At the later stage, retinoic acid may work with WNT and BMP and regulate homeobox containing transcription factors. Finally, there is an overlap in genes dysregulated in Xenopus embryos with median clefts with human genes associated with similar orofacial defects. CONCLUSIONS: This study uncovers novel signaling pathways required for orofacial development as well as pathways that could interact with retinoic acid signaling during the formation of the face. We show that frog faces are an important tool for studying orofacial development and birth defects.

The role of folate metabolism in orofacial development and clefting.

Folate deficiency has been associated with numerous diseases and birth defects including orofacial defects. However, whether folate has a role in the face during early orofacial development has been unclear. The present study reveals that pharmacological and antisense oligonucleotide mediated inhibition of DHFR, an integral enzyme in the folate pathway, results in specific changes in the size and shape of the midface and embryonic mouth. Such defects are accompanied by a severe reduction in the muscle and cartilage jaw elements without significant change in neural crest pattern or global levels of methylation. We propose that the orofacial defects associated with DHFR deficient function are the result of decreased cell proliferation and increased cell death via DNA damage. In particular, localized apoptosis may also be depleting the cells of the face that express crucial genes for the differentiation of the jaw structures. Folate supplementation is widely known to reduce human risk for orofacial clefts. In the present study, we show that activating folate metabolism can reduce median oral clefts in the primary palate by increasing cell survival. Moreover, we demonstrate that a minor decrease in DHFR function exacerbates median facial clefts caused by RAR inhibition. This work suggests that folate deficiencies could be a major contributing factor to multifactorial orofacial defects.

Mammalian target of rapamycin promotes oligodendrocyte differentiation, initiation and extent of CNS myelination.

Prior studies support a role for mammalian target of rapamycin (mTOR) signaling in oligodendrocyte differentiation and myelination. Here we use Cre-recombinase driven by the CNP promoter to generate a mouse line with oligodendrocyte-specific knockdown of mTOR (mTOR cKO) in the CNS. We provide evidence that mTOR is necessary for proper oligodendrocyte differentiation and myelination in the spinal cord. Specifically, the number of mature oligodendrocytes was reduced, and the initiation and extent of myelination were impaired during spinal cord development. Consistent with these data, myelin protein expression, including myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein, and myelin-associated glycoprotein, was delayed in the spinal cord. Hypomyelination of the spinal cord persisted into adulthood, as did the reduction in numbers of mature oligodendrocytes. In the cortex, the structure of myelin appeared normal during development and in the adult; however, myelin protein expression was delayed during development and was abnormal in the adult. Myelin basic protein was significantly reduced in all regions at postnatal day 25. These data demonstrate that mTOR promotes oligodendrocyte differentiation and CNS myelination in vivo and show that the requirement for mTOR varies by region with the spinal cord most dependent on mTOR.