Protein-coding de novo mutations (DNMs) are significant risk factors in many neurodevelopmental disorders, whereas schizophrenia (SCZ) risk associated with DNMs has thus far been shown to be modest. ...We analyzed DNMs from 1,695 SCZ-affected trios and 1,077 published SCZ-affected trios to better understand the contribution to SCZ risk. Among 2,772 SCZ probands, exome-wide DNM burden remained modest. Gene set analyses revealed that SCZ DNMs were significantly concentrated in genes that were highly expressed in the brain, that were under strong evolutionary constraint and/or overlapped with genes identified in other neurodevelopmental disorders. No single gene surpassed exome-wide significance; however, 16 genes were recurrently hit by protein-truncating DNMs, corresponding to a 3.15-fold higher rate than the mutation model expectation (permuted 95% confidence interval: 1-10 genes; permuted P = 3 × 10
). Overall, DNMs explain a small fraction of SCZ risk, and larger samples are needed to identify individual risk genes, as coding variation across many genes confers risk for SCZ in the population.
The common-Pb isotope composition (207Pb/204Pb vs. 206Pb/204Pb) of detrital K-feldspar was measured on the same clastic units from southeastern Laurentia that were previously characterized by ...detrital zircon and detrital monazite geochronology for provenance analysis. The purpose is to test a model that invokes late Paleozoic recycling of sediment initially sourced from erosion of exhuming Grenvillian basement in the Neoproterozoic. The approach takes advantage of the difference in Pb isotope compositions between Laurentian and Amazonian cratonic sources documented by previous workers. Neoproterozoic samples sourced from southern Amazonia and central Laurentian basement that serve as controls on methodology plot within Pb isotope space characteristic of their respective sources. K-feldspar in the Cryogenian Ocoee Supergroup in the southern Appalachian orogen falls within the field of Pb isotope compositions defined by south-central Appalachian basement (SCAB). The latter, in turn, exhibits Pb isotope compositions characteristic of Amazonia, because SCAB was transferred to Laurentia from Amazonia during Rodinian assembly. In contrast, K-feldspar in early Cambrian arenite falls within the Laurentian field, indicating a shift in the early Paleozoic to a sediment source from the Laurentian Craton. K-feldspar in Lower Pennsylvanian lithic arenites of the Central Appalachian Basin exhibit Pb isotope compositions that fall within the SCAB field but at higher Pb isotope ratios than in the inferred Ocoee sources. Incorporation of all provenance constraints requires an immediate source that is isotopically more radiogenic than the Ocoee but similar in all other petrologic and geochronologic characteristics, for example, other Cryogenian to Ediacaran units along strike in the Appalachian orogen. The results further demonstrate the importance of having multiple detrital mineral proxies for accurate provenance analysis rather than using detrital zircon geochronology alone.
A concerted action on the part of international agencies and national governments has resulted in the near-eradication of poliomyelitis. However, both the oral polio vaccine (OPV) and the inactivated ...polio vaccine (IPV) have deficiencies which make them suboptimal for use after global eradication. OPV is composed of attenuated Sabin strains and stimulates robust immunity, but may revert to neurovirulent forms in the intestine which can be shed and infect susceptible contacts. The majority of IPV products are manufactured using pathogenic strains inactivated with formalin. Upon eradication, the production of large quantities of pathogenic virus will present an increased biosecurity hazard. A logical ideal endgame vaccine would be an inactivated form of an attenuated strain that could afford protective immunity while safely producing larger numbers of doses per unit of virus stock than current vaccines. We report here the development of an ionizing radiation (IR)-inactivated Sabin-based vaccine using a reconstituted Mn-decapeptide (MDP) antioxidant complex derived from the radioresistant bacterium Deinococcus radiodurans. In bacteria, Mn2+-peptide antioxidants protect proteins from oxidative damage caused by extreme radiation exposure. Here we show for the first time, that MDP can protect immunogenic neutralizing epitopes in picornaviruses. MDP protects epitopes in Polio Virus 1 and 2 Sabin strains (PV1-S and PV2-S, respectively), but viral genomic RNA is not protected during supralethal irradiation. IR-inactivated Sabin viruses stimulated equivalent or improved neutralizing antibody responses in Wistar rats compared to the commercially used IPV products. Our approach reduces the biosecurity risk of the current PV vaccine production method by utilizing the Sabin strains instead of the wild type neurovirulent strains. Additionally, the IR-inactivation approach could provide a simpler, faster and less costly process for producing a more immunogenic IPV. Gamma-irradiation is a well-known method of virus inactivation and this vaccine approach could be adapted to any pathogen of interest.
Purpose
Cancer survivors’ needs around sexual concerns are often unmet. The primary objective of this systematic review was to examine the prevalence of and factors associated with patient-provider ...communication about sexual concerns in cancer.
Methods
Using PRISMA guidelines, we searched PubMed/MEDLINE, PsychInfo, and CINAHL databases for peer-reviewed quantitative research papers (2000–2015) in cancer samples. Search terms across three linked categories were used (sexuality, communication, and cancer). The National Comprehensive Cancer Network (NCCN) Sexual Function Guidelines were used as a framework to categorize communication reported in each study.
Results
Twenty-nine studies from 10 countries (29 % in USA) were included. Studies assessed patients only (21), providers only (4), and both (4). Communication measures differed across studies and many lacked validity data. When reported by patients or providers, the average prevalence of discussing potential treatment effects on sexual function was 50 (60 % for men and 28 % for women) and 88 %, respectively. As reported by patients or providers, respectively, assessing patients’ sexual concerns (10 and 21 %) and offering treatments (22 and 17 %) were measured in fewer studies and were reported less frequently. Both patients and providers (28 and 32 %, respectively) reported a low prevalence of other non-specific communication. Greater prevalence of communication was associated with male patient gender and more years of provider experience.
Conclusions
Sexual issues go unaddressed for many cancer survivors, particularly women. Both patient and provider interventions are needed.
Implications for Cancer Survivors
Enhancing patient-provider communication about sexual concerns through evidence-based interventions could improve patient sexual function and quality of life.
Retromer controls cellular homeostasis through regulating integral membrane protein sorting and transport and by controlling maturation of the endo-lysosomal network. Retromer dysfunction, which is ...linked to neurodegenerative disorders including Parkinson's and Alzheimer's diseases, manifests in complex cellular phenotypes, though the precise nature of this dysfunction, and its relation to neurodegeneration, remain unclear. Here, we perform an integrated multi-omics approach to provide precise insight into the impact of Retromer dysfunction on endo-lysosomal health and homeostasis within a human neuroglioma cell model. We quantify widespread changes to the lysosomal proteome, indicative of broad lysosomal dysfunction and inefficient autophagic lysosome reformation, coupled with a reconfigured cell surface proteome and secretome reflective of increased lysosomal exocytosis. Through this global proteomic approach and parallel transcriptomic analysis, we provide a holistic view of Retromer function in regulating lysosomal homeostasis and emphasise its role in neuroprotection.
The Pearl River is one of the largest rivers entering the South China Sea, yet its initiation time remains debated, a topic we address using Pb isotopes in detrital K‐feldspar. Based on these Pb ...data, Eocene and Early Oligocene sandstones from the northern South China Sea are interpreted to have been supplied with sediment by proximal rivers draining the Cathaysia Block. In contrast, the Late Oligocene and Miocene sandstones are mainly derived from the western Pearl tributaries (e.g., Hongshui River), suggesting that the Pearl River had formed by the Late Oligocene. Detrital zircon data from the Beibuwan Basin previously suggested that the western tributaries flowed into this basin before being captured by the paleo‐Pearl River. These lines of evidence suggest that progressive headward erosion of the eastern Pearl River and late Oligocene integration of this large fluvial system can be linked to contemporaneous sea‐floor spreading of the South China Sea.
Plain Language Summary
The Pearl River is one of the largest rivers flowing into the South China Sea. However, when this river achieved its present drainage character remains debated. Here we report a comprehensive investigation of sand/sandstone provenance of the Pearl River as well as the Pearl River Mouth Basin (PRMB) using Pb isotopes measured in detrital K‐feldspar. Our results suggest that Eocene and Early Oligocene sandstones were mainly fed by proximal rivers within the Cathaysia Block, while the Late Oligocene samples are enriched in K‐feldspar grains from the Hongshui River, suggesting that the Pearl River had achieved its present character by the Late Oligocene. Early Oligocene deposits in the Beibuwan Basin share an indistinguishable detrital zircon provenance signal to that of the western tributaries of the Pearl River, indicating that the western tributaries likely flowed into the Beibuwan Basin before being captured by the paleo‐Pearl River. Taken together, this evidence suggest that progressive headward erosion of the eastern Pearl River triggered by the subsidence of PRMB and sea‐floor spreading of the South China Sea played an important role in the late Oligocene integration of this large fluvial system.
Key Points
Sedimentary provenance of the Pearl River and Pearl River Mouth Basin constrained using detrital K‐feldspar Pb isotopes
Pb isotopic data indicate that the Pearl River achieved its present character by the Late Oligocene
The opening of the South China Sea played an important role in the drainage reorganization of the Pearl River
Breast cancer survivors treated with anthracycline-based chemotherapy (AC) have increased risk of functional limitation and cardiac dysfunction. We conducted a 12-month randomized controlled trial in ...104 patients with early-stage breast cancer scheduled for AC to determine whether 12 months of exercise training (ExT) could attenuate functional disability (primary end point), improve cardiorespiratory fitness (VO
peak), and prevent cardiac dysfunction.
Women 40 to 75 years of age with stage I to III breast cancer scheduled for AC were randomized to 3 to 4 days per week aerobic and resistance ExT for 12 months (n=52) or usual care (UC; n=52). Functional measures were performed at baseline, at 4 weeks after AC (4 months), and at 12 months, comprising: (1) cardiopulmonary exercise testing to quantify VO
peak and functional disability (VO
peak ≤18.0 mL·kg
·min
); (2) cardiac reserve (response from rest to peak exercise), quantified with exercise cardiac magnetic resonance measures to determine changes in left and right ventricular ejection fraction, cardiac output, and stroke volume; (3) standard-of-care echocardiography-derived resting left ventricular ejection fraction and global longitudinal strain; and (4) biochemistry (troponin and BNP B-type natriuretic peptide).
Among 104 participants randomized, greater study attrition was observed among UC participants (
=0.031), with 93 women assessed at 4 months (ExT, n=49; UC, n=44) and 87 women assessed at 12 months (ExT, n=49; UC, n=38). ExT attenuated functional disability at 4 months (odds ratio, 0.32 95% CI, 0.11-0.94;
=0.03) but not at 12 months (odds ratio, 0.27 95% CI, 0.06-1.12;
=0.07). In a per-protocol analysis, functional disability was prevented entirely at 12 months among participants adherent to ExT (ExT, 0% versus UC, 20%;
=0.005). Compared with UC at 12 months, ExT was associated with a net 3.5-mL·kg
·min
improvement in VO
peak that coincided with greater cardiac output, stroke volume, and left and right ventricular ejection fraction reserve (
<0.001 for all). There was no effect of ExT on resting measures of left ventricular function. Postchemotherapy troponin increased less in ExT than in UC (8-fold versus 16-fold increase;
=0.002). There were no changes in BNP in either group.
In women with early-stage breast cancer undergoing AC, 12 months of ExT did not attenuate functional disability, but provided large, clinically meaningful benefits on VO
peak and cardiac reserve.
URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12617001408370.
We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an ...independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 x 10(-11)), IRF8 (P = 3.73 x 10(-9)) and CD6 (P = 3.79 x 10(-9)). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.
Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point mutations affect many ...chromatin modifications but the exact oncogenic mechanisms are currently unclear. Histone H3.3 is known to localize to nuclear compartments known as promyelocytic leukemia (PML) nuclear bodies, which are frequently mutated and confirmed as oncogenic drivers in acute promyelocytic leukemia.
We find that the pediatric glioma-associated H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to leukemias driven by PML mutations, H3.3-mutated glioma cells are sensitive to drugs that target PML bodies. We also find that point mutations in IDH1/2-which are common events in adult gliomas and myeloid leukemias-also disrupt the formation of PML bodies.
We identify PML as a contributor to oncogenesis in a subset of gliomas and show that targeting PML bodies is effective in treating these H3.3-mutated pediatric gliomas.
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