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Epigenetics and Preeclampsia: Defining Functional Epimutations in the Preeclamptic Placenta Related to the TGF-β Pathway
Preeclampsia is a potentially fatal pregnancy disorder affecting millions of women around the globe. Dysregulation in gene and protein expression within key biological pathways controlling angiogenesis has been implicated in the development of preeclampsia. Altered CpG methylation, a type of epimutation, may underlie this pathway dysregulation. In the present study, placental tissue from preeclamptic cases and normotensive controls was analyzed for genome-wide differential CpG methylation and concomitant changes in gene expression. A set of 123 genes, representing 19.9% of all genes with altered CpG methylation, was associated with functional changes in transcript levels. Underscoring the complex relationships between CpG methylation and gene expression, here hypermethylation was never associated with gene silencing, nor was hypomethylation always associated with gene activation. Moreover, the genomic region of the CpG mark was important in predicting the relationship between CpG methylation and gene expression. The 123 genes were enriched for their involvement in the transforming growth factor beta (TGF-β) signaling pathway, a known regulator of placental trophoblast invasion and migration. This is the first study to identify CpG hypomethylation as an activator of TGF-β-associated gene expression in the preeclamptic placenta. The results suggest functional epimutations are associated with preeclampsia disease status and the identified genes may represent novel biomarkers of disease.
Journal Article
Thinking together : lecturing, learning, and difference in the long nineteenth century
\"Explores the myriad ways that people in the nineteenth century grappled with questions of learning, belonging, civic participation, and deliberation. Focuses on the dynamics of gender, race, region, and religion, and how individuals and groups often excluded from established institutions developed knowledge useful for public life\"--Provided by publisher.
Book
Rapid spin changes around a magnetar fast radio burst
Magnetars are neutron stars with extremely high magnetic fields (≳10
14
gauss) that exhibit various X-ray phenomena such as sporadic subsecond bursts, long-term persistent flux enhancements and variable rotation-period derivative
1
,
2
. In 2020, a fast radio burst (FRB), akin to cosmological millisecond-duration radio bursts, was detected from the Galactic magnetar SGR 1935+2154 (refs.
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–
5
), confirming the long-suspected association between some FRBs and magnetars. However, the mechanism for FRB generation in magnetars remains unclear. Here we report the X-ray observation of two glitches in SGR 1935+2154 within a time interval of approximately nine hours, bracketing an FRB that occurred on 14 October 2022
6
,
7
. Each glitch involved a significant increase in the magnetar’s spin frequency, being among the largest abrupt changes in neutron-star rotation
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–
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observed so far. Between the glitches, the magnetar exhibited a rapid spin-down phase, accompanied by an increase and subsequent decline in its persistent X-ray emission and burst rate. We postulate that a strong, ephemeral, magnetospheric wind
11
provides the torque that rapidly slows the star’s rotation. The trigger for the first glitch couples the star’s crust to its magnetosphere, enhances the various X-ray signals and spawns the wind that alters magnetospheric conditions that might produce the FRB.
X-ray observations of two large glitches bracketing a fast radio burst in the active Galactic magnetar SGR 1935+2154 reveal a connection between rapid spin change and radiative behaviours of the magnetar.
Journal Article
Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated Policy Review from the Southern Network on Adverse Reactions
The EU, the USA, and Japan account for the majority of biological pharmacotherapy use worldwide. Biosimilar regulatory approval pathways were authorised in the EU (2006), in Japan (2009), and in the USA (2015), to facilitate approval of biological drugs that are highly similar to reference products and to encourage market competition. Between 2007 and 2020, 33 biosimilars for oncology were approved by the European Medicines Agency (EMA), 16 by the US Food and Drug Administration (FDA), and ten by the Japan Pharmaceuticals and Medical Devices Agency (PMDA). Some of these approved applications were initially rejected because of manufacturing concerns (four of 36 [11%] with the EMA, seven of 16 [44%] with the FDA, none of ten for the PMDA). Median times from initial regulatory submission before approval of oncology biosimilars were 1·5 years (EMA), 1·3 years (FDA), and 0·9 years (PMDA). Pharmacists can substitute biosimilars for reference biologics in some EU countries, but not in the USA or Japan. US regulation prohibits substitution, unless the biosimilar has been approved as interchangeable, a designation not yet achieved for any biosimilar in the USA. Japan does not permit biosimilar substitution, as prescribers must include the product name on each prescription and that specific product must be given to the patient. Policy Reviews published in 2014 and 2016 in The Lancet Oncology focused on premarket and postmarket policies for oncology biosimilars before most of these drugs received regulatory approval. In this Policy Review from the Southern Network on Adverse Reactions, we identify factors preventing the effective launch of oncology biosimilars. Introduction to the market has been more challenging with therapeutic than for supportive care oncology biosimilars. Addressing region-specific competition barriers and educational needs would improve the regulatory approval process and market launches for these biologics, therefore expanding patient access to these products in the EU, the USA, and Japan.
Journal Article
Fast Discovery of an Extremely Radio-Faint Millisecond Pulsar from the Fermi-Lat Unassociated Source 3fgl J0318.1+0252
High sensitivity radio searches of unassociated γ-ray sources have proven to be an effective way of finding new pulsars. Using the Five-hundred-meter Aperture Spherical radio Telescope (FAST) during its commissioning phase, we have carried out a number of targeted deep searches of Fermi Large Area Telescope (LAT) γ-ray sources. On February 27, 2018 we discovered an isolated millisecond pulsar (MSP), PSR J0318+0253, coincident with the unassociated γ-ray source 3FGL J0318.1+0252. PSR J0318+0253 has a spin period of 5.19 ms, a dispersion measure (DM) of 26 pc cm−3 corresponding to a DM distance of about 1.3 kpc, and a period-averaged flux density of (∼11±2) µJy at L-band (1.05–1.45 GHz). Among all high energy MSPs, PSR J0318+0253 is the faintest ever detected in radio bands, by a factor of at least ∼4 in terms of L-band fluxes. With the aid of the radio ephemeris, an analysis of 9.6 years of Fermi-LAT data revealed that PSR J0318+0253 also displays strong γ-ray pulsations. Follow-up observations carried out by both Arecibo and FAST suggest a likely spectral turn-over around 350 MHz. This is the first result from the collaboration between FAST and the Fermi-LAT teams as well as the first confirmed new MSP discovery by FAST, raising hopes for the detection of many more MSPs. Such discoveries will make a significant contribution to our understanding of the neutron star zoo while potentially contributing to the future detection of gravitational waves, via pulsar timing array (PTA) experiments.
Journal Article
The 'Modernizing Regulatory Review' Memo
On the day he was inaugurated, Pres Biden issued to the heads of all executive departments and agencies a memorandum titled \"Modernizing Regulatory Review.\" The document warrants both praise and criticism. On the one hand, it reinforces longstanding principles of rationality and accountability. On the other, it gives the Office of Information and Regulatory Review a role that the office cannot and should not play. Here, Ray discusses the pros and cons of the memo.
Journal Article