Gene sequencing panels are a powerful diagnostic tool for many clinical presentations associated with genetic disorders. Advances in DNA sequencing technology have made gene panels more economical, ...flexible, and efficient. Because the genes included on gene panels vary widely between laboratories in gene content (e.g., number, reason for inclusion, evidence level for gene–disease association) and technical completeness (e.g., depth of coverage), standards that address technical and clinical aspects of gene panels are needed. This document serves as a technical standard for laboratories designing, offering, and reporting gene panel testing. Although these principles can apply to multiple indications for genetic testing, the primary focus is on diagnostic gene panels (as opposed to carrier screening or predictive testing) with emphasis on technical considerations for the specific genes being tested. This technical standard specifically addresses the impact of gene panel content on clinical sensitivity, specificity, and validity—in the context of gene evidence for contribution to and strength of evidence for gene–disease association—as well as technical considerations such as sequencing limitations, presence of pseudogenes/gene families, mosaicism, transcript choice, detection of copy-number variants, reporting, and disclosure of assay limitations.
The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy ...in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-β superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.
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•Heterochronic parabiosis reverses age-related cardiac hypertrophy•The antihypertrophic effect is not due to hemodynamic or behavioral factors•GDF11 is a circulating TGF-β family member that declines with age•Restoration of youthful GDF11 levels reverses age-related cardiac hypertrophy
Parabiosis experiments in mice unravel a role for the TGF-β family member GDF-11 as a negative regulator of age-associated cardiac hypertrophy.
Thank You to Our Peer Reviewers in 2023 Lugaz, Noe; Carter, Brett; Gannon, Jennifer L. ...
Space weather,
April 2024, 2024-04-00, Letnik:
22, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Key Points
The editors thank the 2023 peer reviewers
Controllable genetic manipulation is an indispensable tool in research, greatly advancing our understanding of cell biology and physiology. However in β-cells, transgene silencing, low inducibility, ...ectopic expression, and off-targets effects are persistent challenges. In this study, we investigated whether an inducible Tetracycline (Tet)-Off system with β-cell-specific mouse insulin promoter (MIP)-itTA-driven expression of tetracycline operon (TetO)-Cre
could circumvent previous issues of specificity and efficacy. Following assessment of tissue-specific gene recombination, β-cell architecture, in vitro and in vivo glucose-stimulated insulin secretion, and whole-body glucose homeostasis, we discovered that expression of any tetracycline-controlled transactivator (e.g., improved itTA, reverse rtTA, or tTA) in β-cells significantly reduced
gene expression and decreased insulin content. This translated into lower pancreatic insulin levels and reduced insulin secretion in mice carrying any tTA transgene, independent of Cre recombinase expression or doxycycline exposure. Our study echoes ongoing challenges faced by fundamental researchers working with β-cells and highlights the need for consistent and comprehensive controls when using the tetracycline-controlled transactivator systems (Tet-On or Tet-Off) for genome editing.
BLOC-one-related complex (BORC) is a multiprotein complex composed of eight subunits named BORCS1-8. BORC associates with the cytosolic face of lysosomes, where it sequentially recruits the small ...GTPase ARL8 and kinesin-1 and -3 microtubule motors to promote anterograde transport of lysosomes toward the peripheral cytoplasm in non-neuronal cells and the distal axon in neurons. The physiological and pathological importance of BORC in humans, however, remains to be determined. Here, we report the identification of compound heterozygous variants missense c.85T>C (p.Ser29Pro) and frameshift c.71-75dupTGGCC (p.Asn26Trpfs*51) and homozygous variants missense c.196A>C (p.Thr66Pro) and c.124T>C (p.Ser42Pro) in BORCS8 in five children with a severe early-infantile neurodegenerative disorder from three unrelated families. The children exhibit global developmental delay, severe-to-profound intellectual disability, hypotonia, limb spasticity, muscle wasting, dysmorphic facies, optic atrophy, leuko-axonopathy with hypomyelination, and neurodegenerative features with prevalent supratentorial involvement. Cellular studies using a heterologous transfection system show that the BORCS8 missense variants p.Ser29Pro, p.Ser42Pro and p.Thr66Pro are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution toward the cell periphery. The BORCS8 frameshift variant p.Asn26Trpfs*51, on the other hand, is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution toward the cell periphery. Therefore, all the BORCS8 variants are partial or total loss-of-function alleles and are thus likely pathogenic. Knockout of the orthologous borcs8 in zebrafish causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease. These findings thus identify BORCS8 as a novel genetic locus for an early-infantile neurodegenerative disorder and highlight the critical importance of BORC and lysosome dynamics for the development and function of the central nervous system.
We review, summarize, and comment on the 2019 National Space Weather Strategy and Action Plan.
Key Points
An updated National Space Weather Strategy and Action Plan is available
The document is ...strongly focused on resilience to space weather effects
Resource commitment is the next big hurdle
To better understand the impact of geomagnetic disturbances on the electric grid, we recreate surface electric fields from two historical geomagnetic storms—the 1989 “Quebec” storm and the 2003 ...“Halloween” storms. Using the Spherical Elementary Current Systems method, we interpolate sparsely distributed magnetometer data across North America. We find good agreement between the measured and interpolated data, with larger RMS deviations at higher latitudes corresponding to larger magnetic field variations. The interpolated magnetic field data are combined with surface impedances for 25 unique physiographic regions from the United States Geological Survey and literature to estimate the horizontal, orthogonal surface electric fields in 1 min time steps. The induced horizontal electric field strongly depends on the local surface impedance, resulting in surprisingly strong electric field amplitudes along the Atlantic and Gulf Coast. The relative peak electric field amplitude of each physiographic region, normalized to the value in the Interior Plains region, varies by a factor of 2 for different input magnetic field time series. The order of peak electric field amplitudes (largest to smallest), however, does not depend much on the input. These results suggest that regions at lower magnetic latitudes with high ground resistivities are also at risk from the effect of geomagnetically induced currents. The historical electric field time series are useful for estimating the flow of the induced currents through long transmission lines to study power flow and grid stability during geomagnetic disturbances.
Key Points
The SECS method is used to interpolate historical magnetic field data
Peak surface electric fields are 2.6 and 1.9 V/km for the 1989 and 2003 storms
Electric fields vary by a factor of 35 for various regional resistivity models
This study aimed to assess the amount and types of clinical genetic testing denied by insurance and the rate of diagnostic and candidate genetic findings identified through research in patients who ...faced insurance denials.
Analysis consisted of review of insurance denials in 801 patients enrolled in a pediatric genomic research repository with either no previous genetic testing or previous negative genetic testing result identified through cross-referencing with insurance prior-authorizations in patient medical records. Patients and denials were also categorized by type of insurance coverage. Diagnostic findings and candidate genetic findings in these groups were determined through review of our internal variant database and patient charts.
Of the 801 patients analyzed, 147 had insurance prior-authorization denials on record (18.3%). Exome sequencing and microarray were the most frequently denied genetic tests. Private insurance was significantly more likely to deny testing than public insurance (odds ratio = 2.03 95% CI = 1.38-2.99 P = .0003). Of the 147 patients with insurance denials, 53.7% had at least 1 diagnostic or candidate finding and 10.9% specifically had a clinically diagnostic finding. Fifty percent of patients with clinically diagnostic results had immediate medical management changes (5.4% of all patients experiencing denials).
Many patients face a major barrier to genetic testing in the form of lack of insurance coverage. A number of these patients have clinically diagnostic findings with medical management implications that would not have been identified without access to research testing. These findings support re-evaluation of insurance carriers’ coverage policies.
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