Spondylocarpotarsal synostosis syndrome is a rare autosomal recessive disorder characterised by vertebral fusions, frequently manifesting as an unsegmented vertebral bar, as well as fusions of the ...carpal and tarsal bones. In a study of three consanguineous families and one non-consanguineous family, linkage analysis was used to establish the chromosomal location of the disease gene. Linkage analysis localised the disease gene to chromosome 3p14. A maximum lod score of 6.49 (q = 0) was obtained for the marker at locus D3S3532 on chromosome 3p. Recombination mapping narrowed the linked region to the 5.7 cM genetic interval between the markers at loci D3S3724 and D3S1300. A common region of homozygosity was found between the markers at loci D3S3724 and D3S1300, defining a physical interval of approximately 4 million base pairs likely to contain the disease gene. Identification of the gene responsible for this disorder will provide insight into the genes that play a role in the formation of the vertebral column and joints.
RNA viruses are a major source of emerging and re-emerging infectious diseases around the world. We developed a method to identify RNA viruses that is based on the fact that RNA viruses produce ...double-stranded RNA (dsRNA) while replicating. Purifying and sequencing dsRNA from the total RNA isolated from infected tissue allowed us to recover dsRNA virus sequences and replicated sequences from single-stranded RNA (ssRNA) viruses. We refer to this approach as dsRNA-Seq. By assembling dsRNA sequences into contigs we identified full length or partial RNA viral genomes of varying genome types infecting mammalian culture samples, identified a known viral disease agent in laboratory infected mice, and successfully detected naturally occurring RNA viral infections in reptiles. Here, we show that dsRNA-Seq is a preferable method for identifying viruses in organisms that don't have sequenced genomes and/or commercially available rRNA depletion reagents. In addition, a significant advantage of this method is the ability to identify replicated viral sequences of ssRNA viruses, which is useful for distinguishing infectious viral agents from potential noninfectious viral particles or contaminants.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Tholeiite of the oldest oceanic crust was drilled during ODP Legs 129 and 185 at Hole 801C in the western Pacific. Fresh appearing submarine basaltic glass (SBG) was recovered from the tholeiites ...(∼167 Ma) which has been shown to be nearly ideal for determining absolute paleointensity. Paleointensities of the younger, off‐axis, alkalic basalts (∼160 Ma), overlying the tholeiites, had been studied earlier. Here we report results from the older tholeiitic (on‐axis) sequence. We subjected a total of 73 specimens from 17 cooling units to absolute paleointensity experiments. Of these, 30 specimens and six cooling unit averages met our strictest reliability criteria, yielding an average of 11.9 ± 3.9 μT. The bulk of evidence suggests a paleolatitude of the site of 14°S (with an uncertainty of 10°). This translates the intensity to a value for the virtual axial dipole moment of 28 ZAm2, slightly lower than values determined from the plagioclase crystals in the three cooling units of the younger alkalic basalts overlying the tholeiites (Tarduno & Cottrell, 2005). Our value is low when compared to the long‐term median value of the field of 42 ZAm2. Our results and those of the published literature therefore support the contention of a low magnetic field strength in the Jurassic (average of 28 ± 14 ZAm2; N = 138 individual estimates), as initially suggested by Prévot et al. (1990). Our interpretation of the body of available data argue for low field strengths for the entire Jurassic extending into the early Cretaceous.
Key Points
We review the literature of Jurassic paleoinensity
We present new paleointensity data for the Jurassic
We support the Mesozoic Dipole Low hypothesis
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Synovial sarcoma is a high-grade soft tissue malignancy characterized by a specific reciprocal translocation t(X;18), which leads to the fusion of the SS18 (SYT) gene to one of three SSX genes (SSX1, ...SSX2 or SSX4). The resulting chimeric SS18-SSX protein is suggested to act as an oncogenic transcriptional regulator. Despite multimodal therapeutic approaches, metastatic disease is often lethal and the development of novel targeted therapeutic strategies is required. Several expression-profiling studies identified distinct gene expression signatures, implying a consistent role of Wnt/β-catenin signaling in synovial sarcoma tumorigenesis. Here we investigate the functional and therapeutic relevance of Wnt/β-catenin pathway activation in vitro and in vivo. Immunohistochemical analyses of nuclear β-catenin and Wnt downstream targets revealed activation of canonical Wnt signaling in a significant subset of 30 primary synovial sarcoma specimens. Functional aspects of Wnt signaling including dependence of Tcf/β-catenin complex activity on the SS18-SSX fusion proteins were analyzed. Efficient SS18-SSX-dependent activation of the Tcf/β-catenin transcriptional complex was confirmed by TOPflash reporter luciferase assays and immunoblotting. In five human synovial sarcoma cell lines, inhibition of the Tcf/β-catenin protein-protein interaction significantly blocked the canonical Wnt/β-catenin signaling cascade, accompanied by the effective downregulation of Wnt targets (AXIN2, CDC25A, c-MYC, DKK1, CyclinD1 and Survivin) and the specific suppression of cell viability associated with the induction of apoptosis. In SYO-1 synovial sarcoma xenografts, administration of small molecule Tcf/β-catenin complex inhibitors significantly reduced tumor growth, associated with diminished AXIN2 protein levels. In summary, SS18-SSX-induced Wnt/β-catenin signaling appears to be of crucial biological importance in synovial sarcoma tumorigenesis and progression, representing a potential molecular target for the development of novel therapeutic strategies.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
IMPORTANCE: A 2010 prospective study of 108 infants estimated the incidence of PHACE (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, eye anomalies) syndrome to be 31% ...in children with facial infantile hemangiomas (IHs) of at least 22 cm2. There is little evidence regarding the associations among IH characteristics, demographic characteristics, and risk of PHACE syndrome. OBJECTIVES: To evaluate demographic characteristics and comorbidities in a large cohort of patients at risk for PHACE syndrome and assess the clinical features of large head and neck IH that may be associated with a greater risk of a diagnosis of PHACE syndrome. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, retrospective cohort study assessed all patients with a facial, head, and/or neck IH who were evaluated for PHACE syndrome from August 1, 2009, to December 31, 2014, at 13 pediatric dermatology referral centers across North America. Data analysis was performed from June 15, 2017, to February 29, 2020. MAIN OUTCOMES AND MEASURES: The main outcome was presence or absence of PHACE syndrome. Data included age at diagnosis, sex, patterns of IH presentation (including size, segment location, and depth), diagnostic procedures and results, and type and number of associated anomalies. RESULTS: A total of 238 patients (mean SD age, 2.96 4.71 months; 184 77.3% female) were included in the analysis; 106 (44.5%) met the criteria for definite (n = 98) or possible (n = 8) PHACE syndrome. A stepwise linear regression model found that a surface area of 25 cm2 or greater (odds ratio OR 2.99; 95% CI, 1.49-6.02) and involvement of 3 or more locations (OR, 17.96; 95% CI, 6.10-52.85) to be statistically significant risk factors for PHACE syndrome. Involvement of the parotid gland (OR, 0.39; 95% CI, 0.18-0.85) and segment S2 (OR, 0.38; 95% CI, 0.16-0.91) was associated with a lower risk. Race and ethnicity may also be associated with PHACE syndrome risk, although more studies are needed. CONCLUSIONS AND RELEVANCE: This cohort study further described factors associated with both a higher and lower risk of PHACE syndrome. The presence of multiple anatomical sites and large surface area were associated with greater risk, whereas S2 or parotid IHs were associated with lower, but still potential, risk. These findings can help in counseling families and decision-making regarding evaluation of infants with large head and neck IHs.
Rationale. Evaluation of the potential allergenicity of proteins derived from genetically modified foods has involved a weight of evidence approach that incorporates an evaluation of protein ...digestibility in pepsin. Currently, there is no standardized protocol to assess the digestibility of proteins using simulated gastric fluid. Potential variations in assay parameters include: pH, pepsin purity, pepsin to target protein ratio, target protein purity, and method of detection. The objective was to assess the digestibility of a common set of proteins in nine independent laboratories to determine the reproducibility of the assay when performed using a common protocol.
Methods. A single lot of each test protein and pepsin was obtained and distributed to each laboratory. The test proteins consisted of Ara h 2 (a peanut conglutin-like protein), β-lactoglobulin, bovine serum albumin, concanavalin A, horseradish peroxidase, ovalbumin, ovomucoid, phosphinothricin acetyltransferase, ribulose diphosphate carboxylase, and soybean trypsin inhibitor. A ratio of 10
U of pepsin activity/μg test protein was selected for all tests (3:1 pepsin to protein, w:w). Digestions were performed at pH 1.2 and 2.0, with sampling at 0.5, 2, 5, 10, 20, 30, and 60
min. Protein digestibility was assessed from stained gels following SDS–PAGE of digestion samples and controls.
Results. Results were relatively consistent across laboratories for the full-length proteins. The identification of proteolytic fragments was less consistent, being affected by different fixation and staining methods. Overall, assay pH did not influence the time to disappearance of the full-length protein or protein fragments, however, results across laboratories were more consistent at pH 1.2 (91% agreement) than pH 2.0 (77%).
Conclusions. These data demonstrate that this common protocol for evaluating the in vitro digestibility of proteins is reproducible and yields consistent results when performed using the same proteins at different laboratories.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Personal genomic educational testing (PGET) has been suggested as a strategy to improve student learning for pharmacogenomics (PGx), but no randomized studies have evaluated PGET’s educational ...benefit. We investigated the effect of PGET on student knowledge, comfort, and attitudes related to PGx in a nonblinded, randomized controlled trial. Consenting participants were randomized to receive PGET or no PGET (NPGET) during 4 subsequent years of a PGx course. All participants completed a pre‐survey and post‐survey designed to assess (1) PGx knowledge, (2) comfort with PGx patient education and clinical skills, and (3) attitudes toward PGx. Instructors were blinded to PGET assignment. The Wilcoxon Rank Sum test was used to compare pre‐survey and post‐survey PGx knowledge, comfort, and attitudes. No differences in baseline characteristics were observed between PGET (n = 117) and NPGET (n = 116) participants. Among all participants, significant improvement was observed in PGx knowledge (mean 57% vs. 39% correct responses; p < 0.001) with similar results for student comfort and attitudes. Change in pre/post‐PGx knowledge, comfort, and attitudes were not significantly different between PGET and NPGET groups (mean 19.5% vs. 16.7% knowledge improvement, respectively; p = 0.41). Similar results were observed for PGET participants carrying a highly actionable PGx variant versus PGET participants without an actionable variant. Significant improvement in Likert scale responses were observed in PGET versus NPGET for questions that assessed student engagement (p = 0.020) and reinforcement of course concepts (p = 0.006). Although some evidence of improved engagement and participation was observed, the results of this study suggest that PGET does not directly improve student PGx knowledge, comfort, and attitudes.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
The sensitivity of the Deep Underground Neutrino Experiment (DUNE) to neutrino oscillation is determined, based on a full simulation, reconstruction, and event selection of the far detector and a ...full simulation and parameterized analysis of the near detector. Detailed uncertainties due to the flux prediction, neutrino interaction model, and detector effects are included. DUNE will resolve the neutrino mass ordering to a precision of 5\(\sigma\), for all \(\delta_{\mathrm{CP}}\) values, after 2 years of running with the nominal detector design and beam configuration. It has the potential to observe charge-parity violation in the neutrino sector to a precision of 3\(\sigma\) (5\(\sigma\)) after an exposure of 5 (10) years, for 50\% of all \(\delta_{\mathrm{CP}}\) values. It will also make precise measurements of other parameters governing long-baseline neutrino oscillation, and after an exposure of 15 years will achieve a similar sensitivity to \(\sin^{2} 2\theta_{13}\) to current reactor experiments.
Transgender populations experience health inequities that underscore the importance of ensuring access to high quality care. We thematically summarize the health care experiences of transgender youth ...living in the southeast United States to identify potential barriers and facilitators to health care.
Transgender youth recruited from community settings in an urban area of the southeast United States participated in individual interviews (n = 33) and focus groups (n = 9) about protective factors. We conducted a thematic analysis of data from 42 participants who described their experiences seeking and receiving health care.
Participants reported a wide range of gender identities. The individual interview sample was majority Black (54.5%) and the mean age was 21.7 years and focus group participants were all white and the mean age was 16.8 years. Participants described numerous barriers to health care, including limited availability of gender affirming care, logistical challenges, such as gatekeeping and cost, concerns about confidentiality in relation to sexual behavior and gender identity, and inadequate cultural competency among providers regarding gender-affirming care. Facilitators included intake procedures collecting chosen pronouns and names and consistent use of them by providers, and open communication, including active listening.
Findings underscore the need for a multi-component approach to ensure both transgender- and youth-friendly care.
Providers and office staff may benefit from transgender cultural competency trainings. In addition, clinic protocols relating to confidentiality and chosen name and pronoun use may help facilitate access to and receipt of quality care.
•We examined transgender youths' experiences with health care in the Southeast.•Barriers to access included limited availability of gender-affirming care.•Facilitators of quality care included consistent use of chosen names and pronouns.•Findings underscore the need to ensure both transgender- and youth-friendly care.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
MicroRNAs (miRNAs) play an important role in development and regulate the expression of many animal genes by post-transcriptional gene silencing. Here we describe the cloning and expression of new ...miRNAs from zebrafish. By high-throughput sequencing of small-RNA cDNA libraries from 5-day-old zebrafish larvae and adult zebrafish brain we found 139 known miRNAs and 66 new miRNAs. For 65 known miRNAs and for 11 new miRNAs we also cloned the miRNA star sequence. We analyzed the temporal and spatial expression patterns for 35 new miRNAs and for 32 known miRNAs in the zebrafish by whole mount in situ hybridization and northern blotting. Overall, 23 of the 35 new miRNAs and 30 of the 32 known miRNAs could be detected. We found that most miRNAs were expressed during later stages of development. Some were expressed ubiquitously, but many of the miRNAs were expressed in a tissue-specific manner. Most newly discovered miRNAs have low expression levels and are less conserved in other vertebrate species. Our cloning and expression analysis indicates that most abundant and conserved miRNAs in zebrafish are now known.
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