Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
18,969
result(s) for
"Hutchinson"
Sort by:
G. Evelyn Hutchinson and the Invention of Modern Ecology
Stephen J. Gould declared G. Evelyn Hutchinson the most important ecologist of the twentieth century. E. O. Wilson pronounced him \"one of the few scientists who could unabashedly be called a genius.\" In this fascinating book, Nancy G. Slack presents for the first time the full life story of this brilliant scientist who was also a master teacher, a polymath, and a delightful friend and correspondent.
Based on full access to Hutchinson's archives and extensive interviews with him and many who knew him, the author evaluates his important contributions to modern ecology and his profound influence as a mentor. Filled with information available nowhere else, the book draws a vibrant portrait of an original scientific thinker who was also a man of remarkable personal appeal.
eBook
Doxycycline decelerates aging in progeria mice
Beyond the antimicrobial activity, doxycycline (DOX) exhibits longevity‐promoting effect in nematodes, while its effect on mammals is unclear. Here, we applied a mouse model of Hutchinson‐Gilford progeria syndrome (HGPS), Zmpste24 knockout (KO) mice, and analyzed the antiaging effect of DOX. We found that the DOX treatment prolongs lifespan and ameliorates progeroid features of Zmpste24 KO mice, including the decline of body and tissue weight, exercise capacity and cortical bone density, and the shortened colon length. DOX treatment alleviates the abnormal nuclear envelope in multiple tissues, and attenuates cellular senescence and cell death of Zmpste24 KO and HGPS fibroblasts. DOX downregulates the level of proinflammatory IL6 in both serum and tissues. Moreover, the elevated α‐tubulin (K40) acetylation mediated by NAT10 in progeria, is rescued by DOX treatment in the aorta tissues in Zmpste24 KO mice and fibroblasts. Collectively, our study uncovers that DOX can decelerate aging in progeria mice via counteracting IL6 expression and NAT10‐mediated acetylation of α‐tubulin. Doxycycline decelerates aging in progeria mice and alleviates cell senescence in Zmpste24 KO MEFs and HGPS fibroblasts, probably via counteracting IL6 expression and NAT10‐mediated tubulin acetylation. This study uncovers the anti‐premature aging effect (“new function”) of the doxycycline (“old” drug), highlighting a safe and affordable therapeutic drug for HGPS.
Journal Article
Primary acquired melanosis with spill over periocular lentigo maligna: 19-year outcomes at a specialist eyelid and ocular oncology centre
Background/aimsThere is a paucity in the literature on the presentation, management and outcomes of cases where primary acquired melanosis (PAM) is associated with spill over/contiguous periocular lentigo maligna (LM). We describe experience of such cases at our eyelid and ocular oncology specialist centre.MethodsWe conducted a retrospective consecutive case review of adult patients with PAM and periocular LM between 2005 and 2024 at Moorfields Eye Hospital in London. Demographic data, diagnosis, histology, imaging, treatment, surgical notes, outcomes and follow-up were collected from the electronic patient record.ResultsOf 21 patients identified, 100% were Caucasian, 13 (62%) were women and the average age of diagnosis was 67 years. Grade of PAM atypia was mild in 5 (24%), moderate in 2 (9%) and severe in 14 (67%) patients. 16 (76%) patients developed melanoma (all types) and 12 (57%) patients developed conjunctival melanoma. Of those with PAM with severe atypia, 93% developed melanoma. The average time interval from diagnosis of PAM and LM to melanoma was 72 months. Melanoma recurrence occurred in 7 (44%) and metastases developed in 4 (25%) patients. Four patients died, including two from metastatic melanoma. Average follow-up length was 129 months.ConclusionsPAM with atypia, particularly severe atypia, when associated with spill over periocular LM, may have significant risk of progression to melanoma. Patients with PAM require careful eyelid examination to identify LM. Management requires multidisciplinary input, urgent biopsy and confocal microscopy if available, lower threshold for treatment and lifelong monitoring.
Journal Article
Endothelial cell‐specific progerin expression does not cause cardiovascular alterations and premature death
Hutchinson‐Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by a mutation in the LMNA gene that provokes the synthesis of progerin, a mutant version of the nuclear protein lamin A that accelerates aging and precipitates death. The most clinically relevant feature of HGPS is the development of cardiac anomalies and severe vascular alterations, including massive loss of vascular smooth muscle cells, increased fibrosis, and generalized atherosclerosis. However, it is unclear if progerin expression in endothelial cells (ECs) causes the cardiovascular manifestations of HGPS. To tackle this question, we generated atherosclerosis‐free mice (LmnaLCS/LCSCdh5‐CreERT2) and atheroprone mice (Apoe−/−LmnaLCS/LCSCdh5‐CreERT2) with EC‐specific progerin expression. Like progerin‐free controls, LmnaLCS/LCSCdh5‐CreERT2 mice did not develop heart fibrosis or cardiac electrical and functional alterations, and had normal vascular structure, body weight, and lifespan. Similarly, atheroprone Apoe−/−LmnaLCS/LCSCdh5‐CreERT2 mice showed no alteration in body weight or lifespan versus Apoe−/−LmnaLCS/LCS controls and did not develop vascular alterations or aggravated atherosclerosis. Our results indicate that progerin expression in ECs is not sufficient to cause the cardiovascular phenotype and premature death associated with progeria. Hutchinson‐Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant protein that is expressed in multiple cell types and accelerates aging, induces cardiovascular disease, and precipitates death. This study shows that mice with progerin expression restricted to endothelial cells do not develop heart fibrosis, cardiac electrical or functional alterations, or aggravated atherosclerosis, and have normal vascular structure, body weight, and lifespan.
Journal Article
Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations
Hutchinson–Gilford 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 β-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.
Journal Article
Baricitinib Augments Lonafarnib Therapy to Preserve Colonic Homeostasis and Microbial Balance in a Mouse Model of Progeria
Hutchinson‐Gilford Progeria Syndrome (HGPS) is a fatal genetic disorder caused by progerin, a mutant lamin A variant that disrupts nuclear architecture and drives systemic cellular dysfunction. Gastrointestinal (GI) involvement in HGPS remains poorly understood, despite growing evidence of gut abnormalities and microbial dysbiosis in progeroid mouse models. Here, we provide the first comprehensive characterization of colonic pathology in LmnaG609G/G609G mice and assess the therapeutic impact of baricitinib (Bar), a JAK–STAT inhibitor, lonafarnib (FTI), the only FDA‐approved therapy, and their combination on colonic health. Bar + FTI combination therapy most effectively lowered progerin levels, preserved colonic architecture and epithelial regeneration markers, while also reducing inflammation, cellular senescence, and early fibrotic changes. Notably, FTI monotherapy aggravated inflammation via STAT1 activation, an effect reversed by Bar co‐administration. Bar also emerged as the primary driver in mitigating colonic tissue senescence, highlighting its role in supporting intestinal homeostasis. In addition, we observed marked microbial dysbiosis in HGPS mice, particularly in late‐stage disease. While both monotherapies induced distinct shifts in gut microbiota, combination therapy preserved a profile more closely resembling healthy controls. These findings expand the current understanding of GI involvement in HGPS and identify the colon as a site where JAK–STAT inhibition enhances the therapeutic profile of FTI. Combined baricitinib and lonafarnib treatment improved colonic pathology in LmnaG609G/G609G progeria mice by reducing progerin, maintaining epithelial regeneration, mitigating inflammation and senescence, and preserving microbiome composition.
Journal Article
miR‐140‐5p Overexpression Contributes to Oxidative Stress and Mitochondrial Dysfunction in Hutchinson‐Gilford Progeria Syndrome Fibroblasts Through NRF2 Pathway
Hutchinson‐Gilford Progeria Syndrome (HGPS) is a rare, fatal genetic disorder characterized by accelerated aging. The accumulation of an abnormal and toxic protein called progerin within HGPS nuclei disrupts cellular processes, including gene expression and DNA repair. Oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defense, is one of the hallmarks of HGPS. To identify novel molecular mechanisms underlying HGPS pathogenesis, we performed miRNA expression profiling in HGPS compared to healthy control fibroblasts. We identified 10 differentially expressed (DE) miRNAs between HGPS and control cells. We focused on miR‐140‐5p and miR‐140‐3p, 2 miRNAs upregulated in HGPS fibroblasts. miR‐140‐5p is known to directly target the transcript of NRF2, a master regulator of the antioxidant response. Using in vitro mimic and antimiR transfections, we demonstrated that miR‐140‐5p overexpression in HGPS fibroblasts results in the downregulation of the NRF2/KEAP1/HO‐1 antioxidant pathway, leading to increased oxidative stress. Furthermore, our results indicate that miR‐140‐5p overexpression induces mitochondrial dysfunction, characterized by a reduced oxidative phosphorylation capacity and affects other hallmarks of aging. By targeting regulation of oxidative stress and mitochondrial function through NRF2, miR‐140‐5p may play a pivotal role in the pathophysiology of HGPS and open new therapeutic avenues. This study identifies a novel molecular mechanism involving miR‐140‐5p that contributes to the pathogenesis of HGPS. By decreasing NRF2 expression, miR‐140‐5p overexpression results in downregulation of the NRF2/KEAP1/HO‐1 antioxidant pathway in HGPS fibroblasts, leading to increased oxidative stress and mitochondrial dysfunction, two hallmarks of aging. (Figure created in BioRender. Magdinier, F. (2025) https://BioRender.com/zixfr1g).
Journal Article