1,127 research outputs found
Cardiac electrical defects in progeroid mice and Hutchinson-Gilford progeria syndrome patients with nuclear lamina alterations
HutchinsonâGilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24-/- mouse model of HGPS. Challenge of Zmpste24-/- mice with the Ă-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery. Patch-clamping in Zmpste24-/- cardiomyocytes revealed prolonged calcium-transient duration and reduced sarcoplasmic reticulum calcium loading and release, consistent with the absence of isoproterenol-induced ventricular arrhythmia. Zmpste24-/- progeroid mice also developed severe fibrosis-unrelated bradycardia and PQ interval and QRS complex prolongation. These conduction defects were accompanied by overt mislocalization of the gap junction protein connexin43 (Cx43). Remarkably, Cx43 mislocalization was also evident in autopsied left ventricle tissue from HGPS patients, suggesting intercellular connectivity alterations at late stages of the disease. The similarities between HGPS patients and progeroid mice reported here strongly suggest that defective cardiac repolarization and cardiomyocyte connectivity are important abnormalities in the HGPS pathogenesis that increase the risk of arrhythmia and premature death.Peer ReviewedPostprint (published version
Clonal hematopoiesis is not prevalent in Hutchinson-Gilford progeria syndrome.
Clonal hematopoiesis of indeterminate potential (CHIP), defined as the presence of somatic mutations in cancer-related genes in blood cells in the absence of hematological cancer, has recently emerged as an important risk factor for several age-related conditions, especially cardiovascular disease. CHIP is strongly associated with normal aging, but its role in premature aging syndromes is unknown. Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare genetic condition driven by the accumulation of a truncated form of the lamin A protein called progerin. HGPS patients exhibit several features of accelerated aging and typically die from cardiovascular complications in their early teens. Previous studies have shown normal hematological parameters in HGPS patients, except for elevated platelets, and low levels of lamin A expression in hematopoietic cells relative to other cell types in solid tissues, but the prevalence of CHIP in HGPS remains unexplored. To investigate the potential role of CHIP in HGPS, we performed high-sensitivity targeted sequencing of CHIP-related genes in blood DNA samples from a cohort of 47 HGPS patients. As a control, the same sequencing strategy was applied to blood DNA samples from middle-aged and elderly individuals, expected to exhibit a biological age and cardiovascular risk profile similar to HGPS patients. We found that CHIP is not prevalent in HGPS patients, in marked contrast to our observations in individuals who age normally. Thus, our study unveils a major difference between HGPS and normal aging and provides conclusive evidence that CHIP is not frequent in HGPS and, therefore, is unlikely to contribute to the pathophysiology of this accelerated aging syndrome.This work was supported by FundaciĂłn âla
Caixaâ (grant number LCF/PR/HR17/52150007 to VF,
and JJF). JJF is supported by a RamĂłn y Cajal award (RYC2016â20026) from the Spanish Ministerio de Ciencia e
InnovaciĂłn (MICIN)/Agencia Estatal de InvestigaciĂłn
(AEI)/10.13039/501100011033 and Fondo Social Europeo âEl
FSE invierte en tu futuroâ. VAâs lab is supported by MICIN/
AEI/10.13039/501100011033 and Fondo Social Europeo âEl
FSE invierte en tu futuroâ (grant number PID2019-108489RBI00), the Progeria Research Foundation (Award PRF 2019â77),
and a donation from AsociaciĂłn Progeria Alexandra Peraut.
LBG is supported by The Progeria Research Foundation. MDD
is supported by a predoctoral FPI fellowship from the Spanish MICIN/AEI/10.13039/501100011033 and Fondo Social
Europeo âEl FSE invierte en tu futuroâ (PRE2019-087463),
and MA-P is supported by a predoctoral FPU contract from the
Ministerio de EducaciĂłn, Cultura y Deporte (FPU18/02913).
The CNIC is supported by the MICIN, the Instituto de Salud
Carlos III, the Pro-CNIC Foundation, and is a Severo Ochoa
Center of Excellence (grant number CEX2020-001041-S
funded by MICIN/AEI/10.13039/501100011033).S
Progress in marine geoconservation in Scotlandâs seas : assessment of key interests and their contribution to Marine Protected Area network planning
This study was part-funded by Marine Scotland and was undertaken as part of the Scottish Marine Protected Areas (MPA) Programme, a joint initiative between Marine Scotland, Historic Scotland, Scottish Natural Heritage (SNH) and the Joint Nature Conservation Committee (JNCC).Geoconservation in the marine environment has been largely overlooked, despite a wealth of accumulated information on marine geology and geomorphology and clear links between many terrestrial and marine features. As part of the wider characterisation of Scotlandâs seas, this study developed criteria and a methodology that follow the established principles of the terrestrial, Great Britain-wide geoconservation audit, the Geological Conservation Review, to assess geodiversity key areas on the seabed. Using an expert judgement approach, eight geodiversity feature categories were identified to represent the geological and geomorphological processes that have influenced the evolution and present-day morphology of the Scottish seabed: Quaternary of Scotland; Submarine Mass Movement; Marine Geomorphology of the Scottish Deep-Ocean Seabed; Seabed Fluid and Gas Seep; Cenozoic Structures of the Atlantic Margin; Marine Geomorphology of the Scottish Shelf Seabed; Coastal Geomorphology of Scotland; and Biogenic Structures of the Scottish Seabed. Within these categories, 35 key areas were prioritised for their scientific value. Specific interests range from large-scale landforms (e.g. submarine landslides, sea-mounts and trenches) to fine-scale dynamic features (e.g. sand waves). Although these geodiversity interests provided supporting evidence for the identification and selection of a suite of Nature Conservation Marine Protected Areas (MPAs) containing important marine natural features, they are only partially represented in these MPAs and existing protected areas. Nevertheless, a pragmatic approach is emerging to integrate as far as possible the conservation management of marine geodiversity with that of biodiversity and based on evidence of the sensitivity and vulnerability geological and geomorphological features on the seabed.PostprintPeer reviewe
\u3cem\u3eDENND5B\u3c/em\u3e Regulates Intestinal Triglyceride Absorption and Body Mass
Regulation of lipid absorption by enterocytes can influence metabolic status in humans and contribute to obesity and related complications. The intracellular steps of chylomicron biogenesis and transport from the Endoplasmic Reticulum (ER) to the Golgi complex have been described, but the mechanisms for post-Golgi transport and secretion of chylomicrons have not been identified. Using a newly generated Dennd5bâ/â mouse, we demonstrate an essential role for this gene in Golgi to plasma membrane transport of chylomicron secretory vesicles. In mice, loss of Dennd5b results in resistance to western diet induced obesity, changes in plasma lipids, and reduced aortic atherosclerosis. In humans, two independent exome sequencing studies reveal that a common DENND5B variant, p.(R52K), is correlated with body mass index. These studies establish an important role for DENND5B in post-Golgi chylomicron secretion and a subsequent influence on body composition and peripheral lipoprotein metabolism
Prospective Safety Surveillance of GH-Deficient Adults: Comparison of GH-Treated vs Untreated Patients.
Context:In clinical practice, the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown.Objective:The objective of this study was to compare adverse events (AEs) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement.Design and Setting:This was a prospective observational study in the setting of US clinical practices.Patients and Outcome Measures:AEs were compared between GH-treated (n = 1988) and untreated (n = 442) GH-deficient adults after adjusting for baseline group differences and controlling the false discovery rate. The standardized mortality ratio was calculated using US mortality rates.Results:After a mean follow-up of 2.3 years, there was no significant difference in rates of death, cancer, intracranial tumor growth or recurrence, diabetes, or cardiovascular events in GH-treated compared with untreated patients. The standardized mortality ratio was not increased in either group. Unexpected AEs (GH-treated vs untreated, P †.05) included insomnia (6.4% vs 2.7%), dyspnea (4.2% vs 2.0%), anxiety (3.4% vs 0.9%), sleep apnea (3.3% vs 0.9%), and decreased libido (2.1% vs 0.2%). Some of these AEs were related to baseline risk factors (including obesity and cardiopulmonary disease), higher GH dose, or concomitant GH side effects.Conclusions:In GH-deficient adults, there was no evidence for a GH treatment effect on death, cancer, intracranial tumor recurrence, diabetes, or cardiovascular events, although the follow-up period was of insufficient duration to be conclusive for these long-term events. The identification of unexpected GH-related AEs reinforces the fact that patient selection and GH dose titration are important to ensure safety of adult GH replacement
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Everolimus rescues multiple cellular defects in laminopathy-patient fibroblasts
LMNA encodes the A-type lamins that are part of the nuclear scaffold. Mutations in LMNA can cause a variety of disorders called laminopathies, including Hutchinson-Gilford progeria syndrome (HGPS), atypical Werner syndrome, and Emery-Dreifuss muscular dystrophy. Previous work has shown that treatment of HGPS cells with the mTOR inhibitor rapamycin or with the rapamycin analog everolimus corrects several of the phenotypes seen at the cellular levelâat least in part by increasing autophagy and reducing the amount of progerin, the toxic form of lamin A that is overproduced in HGPS patients. Since other laminopathies also result in production of abnormal and potentially toxic lamin proteins, we hypothesized that everolimus would also be beneficial in those disorders. To test this, we applied everolimus to fibroblast cell lines from six laminopathy patients, each with a different mutation in LMNA. Everolimus treatment increased proliferative ability and delayed senescence in all cell lines. In several cell lines, we observed that with treatment, there is a significant improvement in nuclear blebbing, which is a cellular hallmark of HGPS and other lamin disorders. These preclinical results suggest that everolimus might have clinical benefit for multiple laminopathy syndromes
Arginase 1 Insufficiency Precipitates Amyloid-\u3cem\u3eÎČ\u3c/em\u3e Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis
Alzheimerâs disease (AD) includes several hallmarks comprised of amyloid-ÎČ (AÎČ) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1fl/fl and LysMcreTg/+ mice crossed with APP Tg2576 mice. Our data indicated that Arg1 haploinsufficiency promoted AÎČ deposition, exacerbated some behavioral impairment, and decreased components of Ragulator-Rag complex involved in mechanistic target of rapamycin complex 1 (mTORC1) signaling and autophagy. Additionally, Arg1 repression and arginine supplementation both impaired microglial phagocytosis in vitro. These data suggest that proper function of Arg1 and arginine metabolism in myeloid cells remains essential to restrict amyloidosis
The Structure of the Oligomerization Domain of Lsr2 from Mycobacterium tuberculosis Reveals a Mechanism for Chromosome Organization and Protection
Lsr2 is a small DNA-binding protein present in mycobacteria and related actinobacteria that regulates gene expression and influences the organization of bacterial chromatin. Lsr2 is a dimer that binds to AT-rich regions of chromosomal DNA and physically protects DNA from damage by reactive oxygen intermediates (ROI). A recent structure of the C-terminal DNA-binding domain of Lsr2 provides a rationale for its interaction with the minor groove of DNA, its preference for AT-rich tracts, and its similarity to other bacterial nucleoid-associated DNA-binding domains. In contrast, the details of Lsr2 dimerization (and oligomerization) via its N-terminal domain, and the mechanism of Lsr2-mediated chromosomal cross-linking and protection is unknown. We have solved the structure of the N-terminal domain of Lsr2 (N-Lsr2) at 1.73 Ă
resolution using crystallographic ab initio approaches. The structure shows an intimate dimer of two ĂâĂâa motifs with no close homologues in the structural databases. The organization of individual N-Lsr2 dimers in the crystal also reveals a mechanism for oligomerization. Proteolytic removal of three N-terminal residues from Lsr2 results in the formation of an anti-parallel ÎČ-sheet between neighboring molecules and the formation of linear chains of N-Lsr2. Oligomerization can be artificially induced using low concentrations of trypsin and the arrangement of N-Lsr2 into long chains is observed in both monoclinic and hexagonal crystallographic space groups. In solution, oligomerization of N-Lsr2 is also observed following treatment with trypsin. A change in chromosomal topology after the addition of trypsin to full-length Lsr2-DNA complexes and protection of DNA towards DNAse digestion can be observed using electron microscopy and electrophoresis. These results suggest a mechanism for oligomerization of Lsr2 via protease-activation leading to chromosome compaction and protection, and concomitant down-regulation of large numbers of genes. This mechanism is likely to be relevant under conditions of stress where cellular proteases are known to be upregulated
The Need for Laboratory Measurements and Ab Initio Studies to Aid Understanding of Exoplanetary Atmospheres
We are now on a clear trajectory for improvements in exoplanet observations
that will revolutionize our ability to characterize their atmospheric
structure, composition, and circulation, from gas giants to rocky planets.
However, exoplanet atmospheric models capable of interpreting the upcoming
observations are often limited by insufficiencies in the laboratory and
theoretical data that serve as critical inputs to atmospheric physical and
chemical tools. Here we provide an up-to-date and condensed description of
areas where laboratory and/or ab initio investigations could fill critical gaps
in our ability to model exoplanet atmospheric opacities, clouds, and chemistry,
building off a larger 2016 white paper, and endorsed by the NAS Exoplanet
Science Strategy report. Now is the ideal time for progress in these areas, but
this progress requires better access to, understanding of, and training in the
production of spectroscopic data as well as a better insight into chemical
reaction kinetics both thermal and radiation-induced at a broad range of
temperatures. Given that most published efforts have emphasized relatively
Earth-like conditions, we can expect significant and enlightening discoveries
as emphasis moves to the exotic atmospheres of exoplanets.Comment: Submitted as an Astro2020 Science White Pape
A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome.
BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is a fatal sporadic autosomal dominant premature ageing disease caused by single base mutations that optimise a cryptic splice site within exon 11 of the LMNA gene. The resultant disease-causing protein, progerin, acts as a dominant negative. Disease severity relies partly on progerin levels. METHODS AND RESULTS: We report a novel form of somatic mosaicism, where a child possessed two cell populations with different HGPS disease-producing mutations of the same nucleotide-one producing severe HGPS and one mild HGPS. The proband possessed an intermediate phenotype. The mosaicism was initially discovered when Sanger sequencing showed a c.1968+2T>A mutation in blood DNA and a c.1968+2T>C in DNA from cultured fibroblasts. Deep sequencing of DNA from the proband's blood revealed 4.7% c.1968+2T>C mutation, and 41.3% c.1968+2T>A mutation. CONCLUSIONS: We hypothesise that the germline mutation was c.1968+2T>A, but a rescue event occurred during early development, where the somatic mutation from A to C at 1968+2 provided a selective advantage. This type of mosaicism where a partial phenotypic rescue event results from a second but milder disease-causing mutation in the same nucleotide has not been previously characterised for any disease.Progeria experiments were funded by The Progeria Research Foundation grants PRF-2002-CB and PRF-2002-MRD (JFB, WEN, SEC, LBG), and by the Medical Research Council UK grant MR/L019116/1 (DL). Core and general laboratory grants are as follows: Kilguss Research Core of Women & Infants Hospital of Rhode Island through an Institutional Development Award from the NIGMS of the NIH (P30GM114750), intramural funds to the NHGRI (ZIA-HG200305), Cancer Research UK programme grant C6/A18796 and Wellcome Trust (WT092096)
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