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Pathogenic germline variants in telomerase ( TERT ) cause telomere biology disorders (TBDs) and are associated with bone marrow failure, pulmonary fibrosis, and other complications. TERT c.3150 G > C (p.K1050N) is frequent in the Ashkenazi Jewish (ASH) population and has been identified in ASH families with TBDs. Whole-genome sequencing of 96 p.K1050N heterozygotes from the UK Biobank and All of Us databases revealed a shared haplotype block, supporting a founder effect. Analyses of 15 additional p.K1050N cases validated this haplotype and identified mitochondrial and Y-STR haplogroups consistent with ASH ancestry. Clinical assessments showed that p.K1050N contributes to TBD phenotypes and shortened telomeres, while population data suggest incomplete penetrance. p.K1050N reduces telomerase activity and processivity, and decreases PCNA expression and BrdU incorporation, impairing cell proliferation. Our findings establish TERT p.K1050N as an ASH founder variant associated with TBDs, underscoring the need for genetic screening and long-term clinical studies.

Background: Population screening can identify genomic risk for medically actionable conditions with onset across the lifespan. In pediatric patients, questions persist regarding the positive healthcare impact of screening for pediatric-onset results and the potential harms of returning adult-onset findings. Purpose: The Pediatric Reporting of Genomic Results Study (PRoGRESS) included an observational cohort study of healthcare behaviors following genomic risk identification in pediatric participants, including completion of recommended management in individuals with pediatric-onset results and inappropriate care in participants with adult-onset findings. Methods: Study participants were recruited via the Geisinger MyCode biobank. Pediatric MyCode participants and at-risk pediatric relatives of adult MyCode participants with actionable genomic findings identified on their research exome were invited to participate in the study before receiving genomic results. Electronic health records of participants with pathogenic/likely pathogenic (P/LP) variants were reviewed for completion of and adherence to recommended care at least 6-month post-results disclosure. Results: Sixty-five participants (age 0.2-18 years) were identified with a P/LP variant in a medically actionable study gene. Thirty-one participants (48%) received a pediatric-onset result; 34 (52%) received an adult-onset result. Thirteen of the 27 participants with pediatric-onset results eligible for management (48%) were adherent to all care; an additional 6 (22%) completed some care. No participants with adult-onset results completed inappropriate care. Conclusions: Most participants who received pediatric-onset results completed some management recommendations, though significant care gaps persisted, highlighting an opportunity to facilitate downstream care. Participants who received adult-onset results did not complete nonrec-ommended care, suggesting this theoretical harm is not being realized. Clinical Trials Registration: NCT03832985. Population screening for genetic variants that increase risk for disease can identify individuals with risk and prompt relevant downstream care to catch diseases early and improve outcomes. Although studies have examined population screening in adults, questions remain regarding the benefits and harms of identifying genetic risk in children. This study examined downstream care in children identified with genomic risk. We were interested in whether children with a pediatric-onset result, for which recommended care begins in childhood, had received recommended care. We also wanted to know whether children with an adult-onset result, for which care is not recommended until adulthood, had received care that would not yet be recommended. We reviewed the completion of recommended care in patients with pediatric-onset results and any inappropriate care in those with adult-onset results. Sixty-five pediatric participants were included in the study. Their medical records were reviewed for care leading up to and for at least 6 months following identification and return of the genetic result. Results demonstrated that pediatric-onset results prompted relevant care, but opportunities remain to ensure that all appropriate care is completed. Adult-onset results did not result in inappropriate care. Keywords: genomic screening; pediatric genetics; cardiovascular genetics; cancer genetics; return of results

Alzheimer’s Disease (AD) is a neuroinflammatory disease characterized partly by the inability to clear, and subsequent build-up, of amyloid-beta (Aβ). AD has a bi-directional relationship with circadian disruption (CD) with sleep disturbances starting years before disease onset. However, the molecular mechanism underlying the relationship of CD and AD has not been elucidated. Myeloid-based phagocytosis, a key component in the metabolism of Aβ, is circadianly-regulated, presenting a potential link between CD and AD. In this work, we revealed that the phagocytosis of Aβ42 undergoes a daily circadian oscillation. We found the circadian timing of global heparan sulfate proteoglycan (HSPG) biosynthesis was the molecular timer for the clock-controlled phagocytosis of Aβ and that both HSPG binding and aggregation may play a role in this oscillation. These data highlight that circadian regulation in immune cells may play a role in the intricate relationship between the circadian clock and AD.

The Stratosphere-troposphere Processes and their Role in Climate (SPARC) Data Initiative (SPARC, 2017) performed the first comprehensive assessment of currently available stratospheric composition measurements obtained from an international suite of space-based limb sounders. The initiative's main objectives were (1) to assess the state of data availability, (2) to compile time series of vertically resolved, zonal monthly mean trace gas and aerosol fields, and (3) to perform a detailed intercomparison of these time series, summarizing useful information and highlighting differences among datasets. The datasets extend over the region from the upper troposphere to the lower mesosphere (300–0.1 hPa) and are provided on a common latitude–pressure grid. They cover 26 different atmospheric constituents including the stratospheric trace gases of primary interest, ozone (O3) and water vapor (H2O), major long-lived trace gases (SF6, N2O, HF, CCl3F, CCl2F2, NOy), trace gases with intermediate lifetimes (HCl, CH4, CO, HNO3), and shorter-lived trace gases important to stratospheric chemistry including nitrogen-containing species (NO, NO2, NOx, N2O5, HNO4), halogens (BrO, ClO, ClONO2, HOCl), and other minor species (OH, HO2, CH2O, CH3CN), and aerosol. This overview of the SPARC Data Initiative introduces the updated versions of the SPARC Data Initiative time series for the extended time period 1979–2018 and provides information on the satellite instruments included in the assessment: LIMS, SAGE I/II/III, HALOE, UARS-MLS, POAM II/III, OSIRIS, SMR, MIPAS, GOMOS, SCIAMACHY, ACE-FTS, ACE-MAESTRO, Aura-MLS, HIRDLS, SMILES, and OMPS-LP. It describes the Data Initiative's top-down climatological validation approach to compare stratospheric composition measurements based on zonal monthly mean fields, which provides upper bounds to relative inter-instrument biases and an assessment of how well the instruments are able to capture geophysical features of the stratosphere. An update to previously published evaluations of O3 and H2O monthly mean time series is provided. In addition, example trace gas evaluations of methane (CH4), carbon monoxide (CO), a set of nitrogen species (NO, NO2, and HNO3), the reactive nitrogen family (NOy), and hydroperoxyl (HO2) are presented. The results highlight the quality, strengths and weaknesses, and representativeness of the different datasets. As a summary, the current state of our knowledge of stratospheric composition and variability is provided based on the overall consistency between the datasets. As such, the SPARC Data Initiative datasets and evaluations can serve as an atlas or reference of stratospheric composition and variability during the “golden age” of atmospheric limb sounding. The updated SPARC Data Initiative zonal monthly mean time series for each instrument are publicly available and accessible via the Zenodo data archive (Hegglin et al., 2020).

The migratory destinations of humpback whales that feed off California, Oregon and Washington were determined using photo-identification. Fluke photographs of 594 individuals were taken between 1981 and 1992 and compared to collections from 9 wintering regions in the North Pacific: Ogasawara (162) and Okinawa (17) islands of Japan; the Big Island and Maui (634 for both) and Kauai (384) of Hawaii; the Revillagigedo Archipelago (450), the mainland coast (383) and Baja Peninsula (471) of Mexico; and Central America (31). A total of 160 matches were found to 6 central and eastern North Pacific wintering regions, with most from Central America, Baja, and mainland Mexico. Of whales identified off Central America, 84% were resighted off California-Washington; this high rate of interchange suggests that whales in these tropical waters appear to be comprised entirely of animals from the California-Washington feeding aggregation. Humpback whales seen off Central America were resighted disproportionately off southern California while those from mainland Mexico tended to be seen off northern California-Washington. From 157 same-season migratory transits documented, the shortest were 29 d to Baja and 56 d to Costa Rica and the longest distance was 5322 km. Of the California-Washington whales with known sex, the proportion of males identified at a wintering region was significantly higher than females (2.2:1, p < 0.05).

Alzheimer’s Disease (AD) is a neuroinflammatory disease characterized partly by the inability to clear, and subsequent build-up, of amyloid-beta (Aβ). Aβ clearance is regulated by several pathways and has a circadian component. However, the mechanism underlying the circadian clearance of Aβ has not been defined. Myeloid-based phagocytosis, a key mechanism in the metabolism of Aβ, is circadianly-regulated, presenting a potential mechanism for the circadian clearance of Aβ. In this work, we revealed that the phagocytosis of Aβ42 undergoes a daily oscillation that is dependent on the circadian clock. We found the circadian timing of global heparan sulfate proteoglycan (HSPG) biosynthesis was the molecular timer for the clock-controlled phagocytosis of Aβ and that both HSPG binding and Aβ42 aggregation were essential for this oscillation. These data highlight that circadian regulation in immune cells may play a role in the intricate relationship between the circadian clock and AD.