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Abstract Study Objectives Melatonin regulates daily rhythms and is important for maintaining a healthy pregnancy. Certain socioeconomic factors may affect melatonin release. This study evaluates whether the increase in melatonin with advancing gestation is associated with social disadvantage. Methods Data were prospectively collected from a socioeconomically diverse cohort of participants with singleton pregnancies (n = 921) at a Midwest academic center. Participants self-collected saliva every four hours over a 24-hour period once per trimester. Diurnal melatonin concentration was measured, and for each trimester, the maximum and mean diurnal melatonin concentration values were obtained. Cosinor-fitting was performed to obtain peak, mesor, and amplitude values, and melatonin profiles were also analyzed by calculating area under the curve. Participants were dichotomized by high and low social disadvantage score (SDS), and diurnal melatonin parameters were compared between participants with high and low SDS. Results Mean diurnal melatonin concentration increased at an average rate of 0.19 pg/mL/week, and amplitude increased by 0.04 pg/mL/week. Participants with high SDS had significantly lower diurnal melatonin concentration amplitudes, means, mesors, and peaks than those with low SDS. Participants with high SDS had a 2.19 [95%CI = 1.94, 2.47] adjusted relative risk for low diurnal amplitude melatonin and had a smaller increase in diurnal melatonin amplitude over weeks of pregnancy than those with low SDS (−0.04 vs. 0.11 pg/mL/week, p<.001). Conclusions Average salivary diurnal melatonin concentration increases across pregnancy, but the degree of increase varies among pregnant participants and is associated with social disadvantage. Statement of Significance During pregnancy, melatonin increases with gestational age and may promote placental homeostasis, fetal maturation, and uterine contractions. In this study, we evaluated whether the increase in melatonin with advancing gestation is modified by social disadvantage. We found that salivary diurnal melatonin concentration mean and amplitude increased as pregnancy progressed, but this increase was blunted or even reversed in participants with high social disadvantage scores. Future research should evaluate strategies to intervene, either via behavioral changes or pharmacologic therapy, to mitigate the negative impacts of social disadvantage on maternal melatonin rhythms.

While there are now numerous records of dinosaurs from Cretaceous rocks around the state of Alaska, very few fossil records of terrestrial vertebrates are known from the Mesozoic rocks of the southwestern part of the state. Here we report the new discovery of extensive occurrences of dinosaur tracks from Aniakchak National Monument of the Alaska Peninsula. These tracks are in the Late Cretaceous (Maastrichtian) Chignik Formation, a cyclic sequence of rocks, approximately 500-600 m thick, representing shallow marine to nearshore marine environments in the lower part and continental alluvial coastal plain environments in the upper part of the section. These rocks are part of the Peninsular Terrane and paleomagnetic reconstructions based on the volcanic rocks of this terrane suggest that the Chignik Formation was deposited at approximately its current latitude which is almost 57° N. Recent field work in Aniakchak National Monument has revealed over 75 new track sites, dramatically increasing the dinosaur record from the Alaska Peninsula. Most of the combined record of tracks can be attributed to hadrosaurs, the plant-eating duck-billed dinosaurs. Tracks range in size from those made by full-grown adults to juveniles. Other tracks can be attributed to armored dinosaurs, meat-eating dinosaurs, and two kinds of fossil birds. The track size of the predatory dinosaur suggests a body approximately 6-7 m long, about the estimated size of the North Slope tyrannosaurid Nanuqsaurus. The larger bird tracks resemble Magnoavipes denaliensis previously described from Denali National Park, while the smaller bird tracks were made by a bird about the size of a modern Willet. Previous interdisciplinary sedimentologic and paleontologic work in the correlative and well-known dinosaur bonebeds of the Prince Creek Formation 1400km-1500km further north in Alaska suggested that high-latitude hadrosaurs preferred distal coastal plain or lower delta plain habitats. The ichnological record being uncovered in the Chignik Formation of southwestern Alaska is showing that the hadrosaur tracks here were also made in distal coastal and delta plain conditions. This similarity may corroborate the habitat preference model for Cretaceous high-latitude dinosaurs proposed for the data gathered from the Prince Creek Formation, and may indicate that at least Beringian hadrosaurids had similar habitat preferences regardless of latitude.

Compared to the osteological record of herbivorous dinosaurs from the Late Cretaceous Prince Creek Formation of northern Alaska, there are relatively fewer remains of theropods. The theropod record from this unit is mostly comprised of isolated teeth, and the only non-dental remains known can be attributed to the troodontid cf. Troodon and the tyrannosaurid Nanuqsaurus. Thus far, the presence of members of Dromaeosauridae has been limited to isolated teeth. Here we describe a symphyseal portion of a small dentary with two ziphodont teeth. Based on tooth shape, denticle morphology, and the position of the Meckelian groove, we attribute this partial dentary to a saurornitholestine dromaeosaurid. The fibrous bone surface, small size, and higher number of mesial denticles compared to distal ones point to a juvenile growth stage for this individual. Multivariate comparison of theropod teeth morphospace by means of principal component analysis reveals an overlap between this dentary and Saurornitholestinae dromaeosaurid morphospace, a result supported by phylogenetic analyses. This is the first confirmed non-dental fossil specimen from a member of Dromaeosauridae in the Arctic, expanding on the role of Beringia as a dispersal route for this clade between Asia and North America. Furthermore, the juvenile nature of this individual adds to a growing body of data that suggests Cretaceous Arctic dinosaurs of Alaska did not undergo long-distance migration, but rather they were year-round residents of these paleopolar latitudes.

Osteolytic lesions (OL) characterize symptomatic multiple myeloma. The mechanisms of how malignant plasma cells (PC) cause OL in one region while others show no signs of bone destruction despite subtotal infiltration remain unknown. We report on a single-cell RNA sequencing (scRNA-seq) study of PC obtained prospectively from random bone marrow aspirates (BM) and paired imaging-guided biopsies of OL. We analyze 148,630 PC from 24 different locations in 10 patients and observe vast inter- and intra-patient heterogeneity based on scRNA-seq analyses. Beyond the limited evidence for spatial heterogeneity from whole-exome sequencing, we find an additional layer of complexity by integrated analysis of anchored scRNA-seq datasets from the BM and OL. PC from OL are characterized by differentially expressed genes compared to PC from BM, including upregulation of genes associated with myeloma bone disease like DKK1 , HGF and TIMP-1 as well as recurrent downregulation of JUN/FOS , DUSP1 and HBB . Assessment of PC from longitudinally collected samples reveals transcriptional changes after induction therapy. Our study contributes to the understanding of destructive myeloma bone disease. Osteolytic lesions (OL) are frequent in multiple myeloma (MM), but are poorly understood. Here, the authors characterise OLs in MM patient samples using single-cell RNA-seq, revealing genes that are specifically regulated in OL compared to random bone marrow aspirates and that reflect the response to induction therapy.

Insomnia is a worldwide problem with substantial deleterious health effects. Twin studies have shown a heritable basis for various sleep-related traits, including insomnia, but robust genetic risk variants have just recently begun to be identified. We conducted genome-wide association studies (GWAS) of soldiers in the Army Study To Assess Risk and Resilience in Servicemembers (STARRS). GWAS were carried out separately for each ancestral group (EUR, AFR, LAT) using logistic regression for each of the STARRS component studies (including 3,237 cases and 14,414 controls), and then meta-analysis was conducted across studies and ancestral groups. Heritability (SNP-based) for lifetime insomnia disorder was significant (h2g = 0.115, p = 1.78 × 10−4 in EUR). A meta-analysis including three ancestral groups and three study cohorts revealed a genome-wide significant locus on Chr 7 (q11.22) (top SNP rs186736700, OR = 0.607, p = 4.88 × 10−9) and a genome-wide significant gene-based association (p = 7.61 × 10−7) in EUR for RFX3 on Chr 9. Polygenic risk for sleeplessness/insomnia severity in UK Biobank was significantly positively associated with likelihood of insomnia disorder in STARRS. Genetic contributions to insomnia disorder in STARRS were significantly positively correlated with major depressive disorder (rg = 0.44, se = 0.22, p = 0.047) and type 2 diabetes (rg = 0.43, se = 0.20, p = 0.037), and negatively with morningness chronotype (rg = −0.34, se = 0.17, p = 0.039) and subjective well being (rg = -0.59, se = 0.23, p = 0.009) in external datasets. Insomnia associated loci may contribute to the genetic risk underlying a range of health conditions including psychiatric disorders and metabolic disease.

One of the proteins most frequently found in neuropathological lesions is the ubiquitin binding protein p62 (sequestosome 1). Post-mortem analysis of p62 is a defining diagnostic marker in several neurodegenerative diseases including amyotrophic lateral sclerosis and inclusion body myositis. Since p62 functions in protein degradation pathways including autophagy, the build-up of p62-positive inclusions suggests defects in protein clearance. p62 was expressed unilaterally in the rat substantia nigra with an adeno-associated virus vector (AAV9) in order to study p62 neuropathology. Inclusions formed within neurons from several days to several weeks after gene transfer. By electron microscopy, the inclusions were found to contain packed 10 nm thick filaments, and mitochondria cristae structure was disrupted, resulting in the formation of empty spaces. In corollary cell culture transfections, p62 clearly impaired mitochondrial function. To probe for potential effects on macroautophagy, we co-expressed p62 with a double fluorescent tagged reporter for the autophagosome protein LC3 in the rat. p62 induced a dramatic and specific dissociation of the two tags. By 12 weeks, a rotational behavior phenotype manifested, consistent with a significant loss of dopaminergic neurons analyzed post-mortem. p62 overexpression resulted in a progressive and robust pathology model with neuronal inclusions and neurodegeneration. p62 gene transfer could be a novel methodological probe to disrupt mitochondrial function or autophagy in the brain and other tissues in vivo.

An understanding of risks to biodiversity is needed for planning action to slow current rates of decline and secure ecosystem services for future human use. Although the IUCN Red List criteria provide an effective assessment protocol for species, a standard global assessment of risks to higher levels of biodiversity is currently limited. In 2008, IUCN initiated development of risk assessment criteria to support a global Red List of ecosystems. We present a new conceptual model for ecosystem risk assessment founded on a synthesis of relevant ecological theories. To support the model, we review key elements of ecosystem definition and introduce the concept of ecosystem collapse, an analogue of species extinction. The model identifies four distributional and functional symptoms of ecosystem risk as a basis for assessment criteria: A) rates of decline in ecosystem distribution; B) restricted distributions with continuing declines or threats; C) rates of environmental (abiotic) degradation; and D) rates of disruption to biotic processes. A fifth criterion, E) quantitative estimates of the risk of ecosystem collapse, enables integrated assessment of multiple processes and provides a conceptual anchor for the other criteria. We present the theoretical rationale for the construction and interpretation of each criterion. The assessment protocol and threat categories mirror those of the IUCN Red List of species. A trial of the protocol on terrestrial, subterranean, freshwater and marine ecosystems from around the world shows that its concepts are workable and its outcomes are robust, that required data are available, and that results are consistent with assessments carried out by local experts and authorities. The new protocol provides a consistent, practical and theoretically grounded framework for establishing a systematic Red List of the world's ecosystems. This will complement the Red List of species and strengthen global capacity to report on and monitor the status of biodiversity.

Hierarchical galaxy formation is the model whereby massive galaxies form from an assembly of smaller units 1 . The most massive objects therefore form last. The model succeeds in describing the clustering of galaxies 2 , but the evolutionary history of massive galaxies, as revealed by their visible stars and gas, is not accurately predicted. Near-infrared observations (which allow us to measure the stellar masses of high-redshift galaxies 3 ) and deep multi-colour images indicate that a large fraction of the stars in massive galaxies form in the first 5 Gyr (refs 4–7 ), but uncertainties remain owing to the lack of spectra to confirm the redshifts (which are estimated from the colours) and the role of obscuration by dust. Here we report the results of a spectroscopic redshift survey that probes the most massive and quiescent galaxies back to an era only 3 Gyr after the Big Bang. We find that at least two-thirds of massive galaxies have appeared since this era, but also that a significant fraction of them are already in place in the early Universe.

The Prince Creek Formation of Alaska, a rock unit that represents lower coastal plain and delta deposits, is one of the most important formations in the world for understanding vertebrate ecology in the Arctic during the Cretaceous. Here we report on an isolated cranial material, supraoccipital, of a lambeosaurine hadrosaurid from the Liscomb Bonebed of the Prince Creek Formation. The lambeosaurine supraoccipital has well-developed squamosal bosses and a short sutural surface with the exoccipital-opisthotic complex, and is similar to lambeosaurine supraoccipitals from the Dinosaur Park Formation in having anteriorly positioned squamosal bosses. Affinities with Canadian lambeosaurines elucidate more extensive faunal exchange between the Arctic and lower paleolatitudes which was previously suggested by the presence of Edmontosaurus , Pachyrhinosaurus , tyrannosaurids, and troodontids in both regions. The presence of one lambeosaurine and nine hadrosaurine supraoccipitals in the Liscomb Bonebed suggests hadrosaurine dominated faunal structure as in the Careless Creek Quarry of the USA that was also deposited under a near-shore environment. It differs from the lambeosaurine dominant structures of localities in Russia and China interpreted as inland environments. This may suggest that lambeosaurines had less preference for near-shore environments than hadrosaurines in both Arctic and lower paleolatitudes.

Holtzman and colleagues identify PARP9-DTX3L as an E3 ubiquitin ligase complex that interacts with STAT1 to modify chromatin accessibility for expression in interferon-stimulated genes and to target viral proteases for degradation. Enhancing the response to interferon could offer an immunological advantage to the host. In support of this concept, we used a modified form of the transcription factor STAT1 to achieve hyper-responsiveness to interferon without toxicity and markedly improve antiviral function in transgenic mice and transduced human cells. We found that the improvement depended on expression of a PARP9-DTX3L complex with distinct domains for interaction with STAT1 and for activity as an E3 ubiquitin ligase that acted on host histone H2BJ to promote interferon-stimulated gene expression and on viral 3C proteases to degrade these proteases via the immunoproteasome. Thus, PARP9-DTX3L acted on host and pathogen to achieve a double layer of immunity within a safe reserve in the interferon signaling pathway.