New Hypothesis for Cause of Epidemic among Native Americans, New England, 1616–1619

This epidemic may have been leptospirosis complicated by Weil syndrome

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

A new model for large-volume low δ18O silicic magmatism? Insights from zircons of the Cougar Point Tuff

The series of multiple supereruptions represented by the Cougar Point Tuff (CPT) of the Bruneau-Jarbidge eruptive center (BJEC) documents the first ~ 2 m.y. of a ~ 5 m.y. interval (~13–8 Ma) of magmatism in the largest low δ18O silicic volcanic province known on Earth. Results of in situ analysis by ion microprobe of oxygen isotope ratios in zircon from 10 units of the CPT (≥ 7,000 km3) indicate characteristic δ18O values < 2‰; available data from Heise and Yellowstone show similarly 18O depleted magmas represent ~45 % and <10 % respectively of total eruptive volumes at these younger volcanic centers of the Yellowstone hotspot track. Combined results of δ18O, U-Th-Pb isotopes and trace elements in zircons distinguish the BJEC from other low δ18O magmatic systems that implicate shallow crustal processes of hydrothermal alteration and cycles of caldera collapse. An initial onset of large volume normal δ18O magmatism is absent at the BJEC; all 10 members of the CPT are strongly depleted in 18O (ave. δ18Ozircon=1.0 ‰) with the third representing the singular occurrence of a super-eruption of magma ≥ 2‰ lower than other large-volume low δ18O magmas known worldwide (δ18OWR ≤ 0.9 ‰ vs. 3.4 ‰). Systematic variations over the sequence of CPT eruptions in the spectrum of intra-unit δ18OZrc and intra-crystal zoning patterns (direction and magnitude of Δ18Ocore-rim), zircon U-Pb ages, and magma temperatures (900-1000°C) and compositions are difficult to reconcile with the model for “cannibalistic” low δ18O magma genesis that has been convincingly argued for Heise and Yellowstone. An alternative model is developed using results of Leeman et al. (2008) for possible degrees of 18O depletion as a function of depth in an extending mid-upper crust that was hydrothermally altered by infiltrating meteoric waters prior to the onset of silicic magmatism. The model proposes that BJEC silicic magmas were generated in response to the propagation of a melting front over a ~ 4 m.y. interval through a crustal volume in which a vertically asymmetric O-isotopic gradient had previously developed. Within the context of the model, CPT zircon data are consistent with events of incremental melting and mixing in roof zones of silicic magma reservoirs during surfaceward advance of the system, and concomitant incremental growth of an underlying vast mafic sill complex

Associations of phthalates, phthalate replacements, and their mixtures with eicosanoid biomarkers during pregnancy

Humans are exposed to complex mixtures of phthalates. Gestational exposure to phthalates has been linked to preeclampsia and preterm birth through potential pathways such as endocrine disruption, oxidative stress, and inflammation. Eicosanoids are bioactive signaling lipids that are related to a variety of homeostatic and inflammatory processes. We investigated associations between urinary phthalates and their mixtures with plasma eicosanoid levels during pregnancy using the PROTECT cohort in Puerto Rico (N = 655). After adjusting for covariates, we estimated pair-wise associations between the geometric mean of individual phthalate metabolite concentrations across pregnancy and eicosanoid biomarkers using multivariable linear regression. We used bootstrapping of adaptive elastic net regression (adENET) to evaluate phthalate mixtures associated with eicosanoids and subsequently create environmental risk scores (ERS) to represent weighted sums of phthalate exposure for each individual. After adjusting for false-discovery, in single-pollutant analysis, 14 of 20 phthalate metabolites or parent compound indices showed significant and primarily negative associations with multiple eicosanoids. In our mixture analysis, associations with several metabolites of low molecular weight phthalates – DEP, DBP, and DIBP – became prominent. Additionally, MEHHTP and MECPTP, metabolites of a new phthalate replacement, DEHTP, were selected as important predictors for determining the concentrations of multiple eicosanoids from different pathway groups. A unit increase in phthalate ERS derived from bootstrapping of adENET was positively associated with several eicosanoids mainly from Cytochrome P450 pathway. For example, an increase in ERS was associated with 11(S)-HETE (β = 1.6, 95% CI: 0.020, 3.180), (±)11,12-DHET (β = 2.045, 95% CI: 0.250, 3.840), 20(S)-HETE (β = 0.813, 95% CI: 0.147, 1.479), and 9 s-HODE (β = 2.381, 95% CI: 0.657, 4.104). Gestational exposure to phthalates and phthalate mixtures were associated with eicosanoid levels during pregnancy. Results from the mixture analyses underscore the complexity of physiological impacts of phthalate exposure and call for further in-depth studies to examine these relationships