Explore the vast range of titles available.

Embryonal rhabdomyosarcomas (ERMS) account for 2–3% of cancers in pediatric and adolescent populations. They are rarer in adults. We and others have reported that ERMS arising in the uterine cervix may harbor mutations in the gene encoding the microRNA biogenesis enzyme, DICER1, but a large series of cases has not been published. In the uterus, distinguishing ERMS from adenosarcoma can be very challenging, even for expert pathologists, and DICER1 alterations have been identified in a variable subset of uterine adenosarcomas. We hypothesized that DICER1 genetic testing may be useful in distinguishing between ERMS and adenosarcoma. We conducted a central pathology review-based study of 64 tumors initially thought to be uterine ERMS or adenosarcoma; 19 neoplasms had a consensus diagnosis of ERMS, 27 of adenosarcoma and for 18, no consensus diagnosis was reached. The median age at diagnosis was 30 years (range 2.5–69) for ERMS, 57.5 years (range 27–82) for adenosarcoma, and 65.5 years (range 32–86) for no consensus cases. In our series, the DICER1 mutation prevalence differed between the three groups: DICER1 alterations were present in 18/19 (95%) ERMS, 7/27 (26%) adenosarcomas ( p  < 0.001), and 4/18 (22%) no consensus cases. A germline alteration was present in 6/12 ERMS patients tested versus 0/6 adenosarcoma patients. Thus, although DICER1 mutations are near ubiquitous in uterine ERMS and are significantly less common in uterine adenosarcoma, DICER1 testing is only of value in distinguishing between the two neoplasms when a DICER1 mutation is absent, as this is helpful in excluding ERMS. On review of the clinical and radiological features of the single DICER1 wild-type cervical ERMS, this was thought most likely to be of vaginal origin. Given the significant prevalence of DICER1 germline pathogenic variants in uterine ERMS, all patients with this diagnosis should be referred to a genetics service.

DICER1 tumor predisposition syndrome (DTPS) is a mainly childhood onset tumour predisposition disease. This genetic disorder is caused by germline pathogenic variants in the DICER1 gene, the product of which plays a crucial role in the biogenesis of micro (mi)RNAs. In most cases, an initial germline loss of function variant in DICER1 predisposes an individual to develop this genetic disease. A second somatic missense variant occurring within exons encoding the RNase IIIb domain of this gene is then required for tumorigenesis. Usually, the first germline variant is a nonsense or frameshift variant that is predicted to produce a truncated DICER1 protein. Interestingly, there is a subset of persons who appear to be affected by this disorder but harbor germline missense variants predicted to produce full-length DICER1 protein. These variants cluster in the Platform domain of the DICER1 protein, which is responsible for binding to the 5’ phosphate of precursor (pre)-miRNAs.We decided to investigate the pathogenicity of 10 missense variants located in the Platform domain and two variants located in the adjacent PAZ domain. An in vitro cleavage assay identified four variants (p.G803R, p.L805P, p.S839F, and p.L881P) as impacting the ability of DICER1 to cleave pre-miRNAs. Interestingly, these variants cluster in a hydrophobic core of the Platform domain. miRNA profiling of a set of DICER1-complemented murine mesenchymal stem cell lines further showed that these variants produce an altered cellular miRNA profile. These miRNA profiling data were validated by a series of reporter mRNA assays. We then discovered that the impaired cleavage exhibited by these select DICER1 variants was attributed to the their reduced abilities to bind to pre-miRNAs, as demonstrated by competition and electrophoretic mobility shift assays. In support of the results from the biochemical assays, molecular genetic analysis of biological samples, combined with clinical data from patients bearing these four variants gave results that were consistent with classification of theses variants as pathogenic for DTPS

DICER1 tumor predisposition syndrome is a pleiotropic disorder that gives rise to various mainly pediatric-onset lesions. We report an extraskeletal chondroma (EC) of the great toe occurring in a child who, unusually, carries a germline “hotspot” missense DICER1 variant rather than the more usual loss-of-function (LOF) variant. No heterozygous LOF allele was identified in the EC. We demonstrate this variant impairs 5p cleavage of precursor-miRNA (pre-miRNA) and competes with wild-type (WT) DICER1 protein for pre-miRNA processing. These results suggest a mechanism through which a germline RNase IIIb variant could impair pre-miRNA processing without complete LOF of the WT DICER1 allele.

Genetic analyses of samples obtained from two children with mesenchymal hamartomas of the liver (MHLs) implicate variant DICER1 as a cause and MHL as a phenotype of the DICER1 syndrome. DICER1 is an enzyme that processes microRNAs.

Lynch syndrome is an autosomal dominant disorder that usually results from a pathogenic germline variant in one of four genes (MSH2, MSH6, MLH1, PMS2) involved in DNA mismatch repair. Carriers of such variants are at risk of developing numerous cancers during adulthood. Here we report on a family suspected of having Lynch syndrome due to a history of endometrial adenocarcinoma, ovarian clear cell carcinoma, and adenocarcinoma of the duodenum in whom we identified a germline 29 nucleotide in-frame inversion in exon 3 of MSH2. We further show that this variant is almost completely absent at the protein level, and that the associated cancers have complete loss of MSH2 and MSH6 expression by immunohistochemistry. Functional investigation of this inversion in a laboratory setting revealed a resultant abnormal protein function. Thus, we have identified an unusual, small germline inversion in a mismatch repair gene that does not lead to a premature stop codon yet appears likely to be causal for the observed cancers.

The purpose of this study is to examine colleges’ and universities’ compliance with the criteria presented by the Sexual Assault and Violence Education Act ( SaVE ). Using a stratified random sample of postsecondary institutions ( n  = 435), we examined university websites in spring 2015 to determine whether schools were meeting each criterion of the SaVE Act . Additionally, we also examined what types of programs were offered for prevention, the accessibility of the information (by number of separations from universities main website). Lastly, we examined how university resources and programs, as well as institutional and student characteristics, were related to overall compliance and the availability of online information on sexual violence programs that institutions offered. Findings showed that only 11 % of schools within the sample were fully compliant with the requirements of the SaVE Act and on average, each school met ten of the eighteen criteria for compliance. Most resources were available within websites that were three to four separations from the main university page. Student population and region were positively associated with whether any programs on sexual violence programs were offered and schools with women’s centers were more likely to offer program/s on dating/domestic violence. Additionally, ROTC programs and larger student populations were positively associated with compliance, while being located in the south was negatively associated.

For the last thirty years, researchers have attempted to make sense of the problematic nature of crime on college campuses, while legislators use the benefits of the legislator to implement laws that require universities to address these problems. However, there still exists a problem of crime on college campuses, specifically sexual assault. The largest sub-category of sexual assault on college campuses comes from those who are victimized by persons that they know. Because of this frequency of an individual being sexually assaulted by a friend, someone they are/were dating, or an acquaintance, it is vital that students are able to be informed about date and acquaintance rape and sexual assault. This study diagnoses the availability of information on 424 college campuses within the United States. What is found throughout this research is that less than half of all universities in the sample make some form of information available on their webpage addressing date or acquaintance rape and sexual assault. While this is alarming, there are policy implications and future research that can continue to make information less of a trend and reverse course to make students more knowledgeable about date and acquaintance rape and sexual assault.

In human, the Parkin Co-Regulated Gene (PACRG) shares a bidirectional promoter with Parkin, a gene involved in Parkinson's disease, mitochondrial quality control and inflammation. The PACRG protein is essential to the formation of the inner junction between doublet microtubules of the axoneme, a structure found in flagella and cilia. PACRG interacts with tubulin as well as the meiosis expressed gene 1 (MEIG1) protein, which is essential for spermiogenesis in mice. However, the 3D structure of human PACRG is unknown. Here, we report the crystal structure of the C-terminal domain of human PACRG in complex with MEIG1 at 2.1 Å resolution. PACRG adopts an α-helical structure with a loop insertion that mediates a conserved network of interactions with MEIG1. Using the cryo-electron tomography structure of the axonemal doublet microtubule from the flagellated protozoan Chlamydomonas reinhardtii, we generate a model of a mammalian microtubule doublet inner junction, which reveals how PACRG interacts with tubulin subunits in both the A- and B-tubules. Furthermore, the model shows that MEIG1 interacts with β-tubulin on the outer surface of the B-tubule, facing towards the central pair of the axoneme where it can bind to proteins in this region. We also model the PACRG-like protein (PACRGL), a homolog of PACRG with potential roles in microtubule remodelling and axonemal inner junction formation. Finally, we explore the evolution of the PACRG and Parkin head-to-head gene structure and analyze the tissue distribution of their transcripts. Our work establishes a framework to assess the function of the PACRG family of proteins and its adaptor proteins in the function of motile and non-motile cilia.

In the future, Earth will be warmer, precipitation events will be more extreme, global mean sea level will rise, and many arid and semiarid regions will be drier. Human modifications of landscapes will also occur at an accelerated rate as developed areas increase in size and population density. We now have gridded global forecasts, being continually improved, of the climatic and land use changes (C&LUC) that are likely to occur in the coming decades. However, besides a few exceptions, consensus forecasts do not exist for how these C&LUC will likely impact Earth‐surface processes and hazards. In some cases, we have the tools to forecast the geomorphic responses to likely future C&LUC. Fully exploiting these models and utilizing these tools will require close collaboration among Earth‐surface scientists and Earth‐system modelers. This paper assesses the state‐of‐the‐art tools and data that are being used or could be used to forecast changes in the state of Earth's surface as a result of likely future C&LUC. We also propose strategies for filling key knowledge gaps, emphasizing where additional basic research and/or collaboration across disciplines are necessary. The main body of the paper addresses cross‐cutting issues, including the importance of nonlinear/threshold‐dominated interactions among topography, vegetation, and sediment transport, as well as the importance of alternate stable states and extreme, rare events for understanding and forecasting Earth‐surface response to C&LUC. Five supplements delve into different scales or process zones (global‐scale assessments and fluvial, aeolian, glacial/periglacial, and coastal process zones) in detail. Key Points We review models and data useful for forecasting Earth surface changes We identify key knowledge gaps required to forecast Earth surface changes We strategize how geomorphologists and Earth‐systems modelers can collaborate

Abstract Managing wildlife populations in the face of global change requires regular data on the abundance and distribution of wild animals, but acquiring these over appropriate spatial scales in a sustainable way has proven challenging. Here we present the data from Snapshot USA 2020, a second annual national mammal survey of the USA. This project involved 152 scientists setting camera traps in a standardized protocol at 1485 locations across 103 arrays in 43 states for a total of 52,710 trap‐nights of survey effort. Most (58) of these arrays were also sampled during the same months (September and October) in 2019, providing a direct comparison of animal populations in 2 years that includes data from both during and before the COVID‐19 pandemic. All data were managed by the eMammal system, with all species identifications checked by at least two reviewers. In total, we recorded 117,415 detections of 78 species of wild mammals, 9236 detections of at least 43 species of birds, 15,851 detections of six domestic animals and 23,825 detections of humans or their vehicles. Spatial differences across arrays explained more variation in the relative abundance than temporal variation across years for all 38 species modeled, although there are examples of significant site‐level differences among years for many species. Temporal results show how species allocate their time and can be used to study species interactions, including between humans and wildlife. These data provide a snapshot of the mammal community of the USA for 2020 and will be useful for exploring the drivers of spatial and temporal changes in relative abundance and distribution, and the impacts of species interactions on daily activity patterns. There are no copyright restrictions, and please cite this paper when using these data, or a subset of these data, for publication.