The Last Fossil Primate in North America, New Material of the Enigmatic \u3ci\u3eEkgmowechashala\u3c/i\u3e From the Arikareean of Oregon

OBJECTIVE: Primates were common in North America through most of the Eocene, but vanished in the Chadronian, about 35 million years ago. In the Arikareean, about 6 million years later, the enigmatic primate Ekgmowechashala appeared in the Great Plains and Oregon. This taxon shows little resemblance to other North American primates and its phylogenetic position has long been debated. New material of this taxon allows a revised assessment of its age and how it is related to other primates. METHODS: Recently collected Ekgmowechashala specimens from the Turtle Cove Member of the John Day Formation in Oregon are described. These specimens are compared to previously collected material from South Dakota and Nebraska, as well as other fossil primates from North America and Asia. RESULTS: Study of the John Day material allows diagnosis of a new, distinct species. Comparison of Ekgmowechashala to a pair of recently described Asian primates, Muangthanhinius and Bugtilemur, suggests that it is a strepsirrhine adapiform, rather than an omomyid. The well-defined stratigraphy and dated marker beds of the Turtle Cove Member provide a refined age for Ekgmowechashala occurrences in Oregon, during the Oligocene (early Arikareean). CONCLUSIONS: The age and morphology of these ekgmowechashaline taxa suggest that the group originated in Asia and dispersed to North America in the Oligocene, after the extinction of other primates in North America. Contemporaneous occurrences of Ekgmowechashala in Oregon and the Great Plains indicate the last non-human primates vanished in North America about 26 million years ago

A new lower Turonian mosasaurid from the Western Interior Seaway and the antiquity of the unique basicranial circulation pattern in Plioplatecarpinae

We describe and name a new mosasaur taxon, Sarabosaurus dahli gen. et sp. nov., from the lower Turonian part of the Tropic Shale in Utah, USA. The holotype specimen preserves significant portions of the skull and axial postcranial skeleton. It was found in the upper part of the Watinoceras devonense Ammonite Zone, bounded by radioisotopic dates above and below, and is thus about 93.7 Ma, the oldest mosasaurid taxon known from the Western Interior Seaway. The new taxon possesses a vascular pattern of the basisphenoid heretofore only seen in late diverging plioplatecarpine mosasaurids. Reevaluation of the morphology of the basisphenoid of previously described Turonian mosasaurs using μCT techniques reveals the derived condition is also present in Yaguasaurus and the incipient condition in Tethysaurus and Russellosaurus. In these two taxa, the canals enter the basisphenoid, but do not pass into the basioccipital. Instead, they exit only high on the posterior wall of the sella turcica, in a position similar to the basilar artery of other lizards. This vascular pattern, both in its incipient and derived states, is unique among squamates and supports inclusion of the aforementioned taxa in a monophyletic Plioplatecarpinae, for which we provide an emended diagnosis. Phylogenetic analysis recovers Sarabosaurus dahli gen. et sp. nov. as the sister taxon to Yaguarasaurus and all other later diverging plioplatecarpines, with Russellosaurus and Tethysaurus as successive sister taxa. Tylosaurine mosasaurids retain the primitive condition of the basisphenoid vascularization pattern and implies a tylosaurine-plioplatecarpine divergence in the late Cenomanian or earliest Turonian

Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation

Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale—Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale—Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2–6 and 9–15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2–6 months and 25.7% at 9–15 months. At 9–15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9–15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2–6 months; this failed to reach significance at 9–15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes

An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk

Abstract: It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG sites associated with PrCa risk, here we establish genetic models to predict methylation (N = 1,595) and conduct association analyses with PrCa risk (79,194 cases and 61,112 controls). We identify 759 CpG sites showing an association, including 15 located at novel loci. Among those 759 CpG sites, methylation of 42 is associated with expression of 28 adjacent genes. Among 22 genes, 18 show an association with PrCa risk. Overall, 25 CpG sites show consistent association directions for the methylation-gene expression-PrCa pathway. We identify DNA methylation biomarkers associated with PrCa, and our findings suggest that specific CpG sites may influence PrCa via regulating expression of candidate PrCa target genes

Evaluating Approaches for Constructing Polygenic Risk Scores for Prostate Cancer in Men of African and European Ancestry

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction