scholarly journals The role of mutational spectrum in the selection against mutator alleles

2019 ◽  
Author(s):  
Alejandro Couce ◽  
Olivier Tenaillon
Keyword(s):  
Bacterial Genome ◽  
Clinical Settings ◽  
Disruptive Effect ◽  
Genome Wide ◽  
Complex Picture ◽  
Order Of Magnitude ◽  
Evolution Experiment ◽  
History Of

AbstractRapidly adapting microbe and cancer cell populations often evolve high mutation rates. Yet, once adaptive opportunity declines, antimutator alleles are expected to take over as a result of indirect selection against deleterious mutations. Theory indicates that the most important determinant of antimutator invasions is the extent of mutation rate reduction. However, inconsistent results from evolution experiments suggest that additional factors may also play a major role in antimutator dynamics. Here we show that the idiosyncratic mutation bias exhibited by different mutators – a previously unrecognized factor – can greatly alter mutator susceptibility to antimutator invasions. Using a simulation model calibrated to mimic a well-known long-term evolution experiment with bacteria, we show that differences in average deleterious load can account for order-of-magnitude changes in antimutator fitness for a realistic range of parameters. Since these parameters are known to vary with the environment, our results reveal an unanticipated source of variability in antimutator dynamics. Finally, we estimated the genome-wide average disruptive effect on proteins of mutations caused by different mutators, and found marked and systematic differences emerging across mutators and species with different genomic GC compositions. Taken together, our results suggest that antimutator dynamics may be highly dependent on the specific genetic, ecological and evolutionary history of a given population. Such dependence reveals a more complex picture than anticipated, being relevant for understanding mutators in clinical settings, as well as how hypermutability shapes the evolution of bacterial genome size and composition.

Differences in telomere length between patients with bipolar disorder and controls are influenced by lithium treatment

2020 ◽  
Vol 21 (8) ◽  
pp. 533-540 ◽  
Author(s):  
Claudia Pisanu ◽  
Donatella Congiu ◽  
Mirko Manchia ◽  
Paola Caria ◽  
Cristina Cocco ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Telomere Length ◽  
Lithium Treatment ◽  
Telomere Shortening ◽  
Genome Wide ◽  
History Of ◽  
Genetically Determined ◽  
The Relationship

Aim: To assess the role of lithium treatment in the relationship between bipolar disorder (BD) and leukocyte telomere length (LTL). Materials & methods: We compared LTL between 131 patients with BD, with or without a history of lithium treatment, and 336 controls. We tested the association between genetically determined LTL and BD in two large genome-wide association datasets. Results: Patients with BD with a history lithium treatment showed longer LTL compared with never-treated patients (p = 0.015), and similar LTL compared with controls. Patients never treated with lithium showed shorter LTL compared with controls (p = 0.029). Mendelian randomization analysis showed no association between BD and genetically determined LTL. Conclusion: Our data support previous findings showing that long-term lithium treatment might protect against telomere shortening.

scholarly journals Pediatric Antiphospholipid Syndrome: from Pathogenesis to Clinical Management

2021 ◽  
Vol 23 (2) ◽  
Author(s):  
Silvia Rosina ◽  
Cecilia Beatrice Chighizola ◽  
Angelo Ravelli ◽  
Rolando Cimaz
Keyword(s):  
Antiphospholipid Syndrome ◽  
Fluid Phase ◽  
Multiple Organ ◽  
Clinical Settings ◽  
Glycoprotein I ◽  
Long Term Follow Up ◽  
Pediatric Populations ◽  
Cellular Components

Abstract Purpose of Review Elucidating the pathogenic mechanisms mediated by antiphospholipid antibodies (aPL) might exert important clinical implications in pediatric antiphospholipid syndrome (APS). Recent Findings aPL are traditionally regarded as the main pathogenic players in APS, inducing thrombosis via the interaction with fluid-phase and cellular components of coagulation. Recent APS research has focused on the role of β2 glycoprotein I, which bridges innate immunity and coagulation. In pediatric populations, aPL should be screened in appropriate clinical settings, such as thrombosis, multiple-organ dysfunction, or concomitant systemic autoimmune diseases. Children positive for aPL tests often present non-thrombotic non-criteria manifestations or asymptomatic aPL positivity. In utero aPL exposure has been suggested to result in developmental disabilities, warranting long-term follow-up. Summary The knowledge of the multifaceted nature of pediatric APS should be implemented to reduce the risk of underdiagnosing/undertreating this condition. Hopefully, recent pathogenic insights will open new windows of opportunity in the management of pediatric APS.

Effects of long-term chloroquine administration on the natural history of aortic aneurysms in mice

2015 ◽  
Vol 93 (8) ◽  
pp. 641-648 ◽  
Author(s):  
Azza Ramadan ◽  
Mark D. Wheatcroft ◽  
Adrian Quan ◽  
Krishna K. Singh ◽  
Fina Lovren ◽  
...  
Keyword(s):  
Natural History ◽  
Thrombus Formation ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Suprarenal Aorta ◽  
History Of ◽  
Categorical Distribution

Autophagy regulates cellular homeostasis and integrates the cellular pro-survival machinery. We investigated the role of autophagy in the natural history of murine abdominal aortic aneurysms (AAA). ApoE−/− mice were implanted with saline- or angiotensin II (Ang-II)-filled miniosmotic pumps then treated with either the autophagy inhibitor chloroquine (CQ; 50 mg·(kg body mass)–1·day–1, by intraperitoneal injection) or saline. Ang-II-elicited aneurysmal expansion of the suprarenal aorta coupled with thrombus formation were apparent 8 weeks later. CQ had no impact on the incidence (50% for Ang-II compared with 46.2% for Ang-II + CQ; P = NS) and categorical distribution of aneurysms. The markedly reduced survival rate observed with Ang-II (57.1% for Ang-II compared with 100% for saline; P < 0.05) was unaffected by CQ (61.5% for Ang-II + CQ; P = NS compared with Ang-II). CQ did not affect the mean maximum suprarenal aortic diameter (1.91 ± 0.19 mm for Ang-II compared with 1.97 ± 0.21 mm for Ang-II + CQ; P = NS). Elastin fragmentation, collagen accumulation, and smooth muscle attrition, which were higher in Ang-II-treated mice, were unaffected by CQ treatment. Long-term CQ administration does not affect the natural history and prognosis of experimental AAA, suggesting that global loss of autophagy is unlikely to be a causal factor in the development of aortic aneurysms. Manipulation of autophagy as a mechanism to reduce AAA may need re-evaluation.

scholarly journals Between communism and capitalism: long-term inequality in Poland, 1892–2015

2021 ◽  
Author(s):  
Paweł Bukowski ◽  
Filip Novokmet
Keyword(s):  
Household Survey ◽  
National Accounts ◽  
Capital Income ◽  
Sharp Rise ◽  
Long Run ◽  
History Of ◽  
Low Levels ◽  
Distribution Of Income

AbstractWe construct the first consistent series on the long-term distribution of income in Poland by combining tax, household survey and national accounts data. We document a U-shaped evolution of inequalities from the end of the nineteenth century until today: (1) inequality was high before WWII; (2) abruptly fell after the introduction of communism in 1947 and stagnated at low levels during the whole communist period; (3) experienced a sharp rise with the return to capitalism in 1989. We find that official survey-based measures strongly under-estimate the rise in inequality since 1989. Our results highlight the prominent role of capital income in driving the U-shaped evolution of top income shares. The unique inequality history of Poland speaks to the central role of institutions and policies in shaping inequality in the long run.

Archaeology of a Piece of Gondwanaland

2015 ◽  
Author(s):  
Christophe Sand
Keyword(s):  
Cultural Change ◽  
New Caledonia ◽  
Human Settlement ◽  
European Contact ◽  
Cultural Complex ◽  
Geological Diversity ◽  
History Of ◽  
Colonial Settlement

New Caledonia is the southern-most archipelago of Melanesia. Its unique geological diversity, as part of the old Gondwana plate, has led to specific pedological and floral environments that have, since first human settlement, influenced the ways Pacific Islanders have occupied and used the landscape. This essay presents some of the key periods of the nearly 3,000 years of pre-colonial human settlement. After having presented a short history of archaeological research in New Caledonia, the essay focuses first on the Lapita foundation, which raises questions of long-term contacts and cultural change. The second part details the unique specificities developed during the “Traditional Kanak Cultural Complex,” during the millennium predating first European contact, as well as highlighting the massive changes brought by the introduction of new diseases, in the decades before the colonial settlement era. This leads to questions about archaeological history and the role of archaeology in the present decolonizing context.

The Role of ECT in Schizophrenia

2002 ◽  
Vol 10 (4) ◽  
pp. 385-388 ◽  
Author(s):  
Richard Keuneman ◽  
Rajiv Weerasundera ◽  
David Castle
Keyword(s):  
Acute Onset ◽  
Clinical Settings ◽  
Limited Data ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Affective Symptoms ◽  
Maintenance Ect ◽  
The Subject

Objective: To review the place of electroconvulsive therapy (ECT) in the treatment of schizophrenia. Conclusions: ECT is as effective, if not more so, than the antipsychotic drugs in certain clinical settings. It can be rapidly effective in acute episodes. When used alone, antipsychotics have comparable or superior efficacy to ECT alone in the short term. However, ECT possibly confers better long-term outcome. Combination treatment with antipsychotic medications and ECT is superior to either treatment alone, and is safe and effective, notably in medication resistant schizophrenia. Benefits of acute courses of ECT may be short-lived unless maintenance ECT is instituted, although there are limited data on the subject. Clinically, patients with acute onset, shorter episodes are more likely to respond to ECT. Catatonia, preoccupation with delusions and hallucinations, and a relative absence of premorbid schizoid and paranoid personality traits, are other clinical factors less strongly predictive of positive response. The presence of affective symptoms is often thought to be predictive of clinical response. However, there is little research evidence for this. While medications remain the mainstay of treatment in schizophrenia, ECT does have a clear and increasingly recognised role which requires further evaluation.

scholarly journals Cosmogenic burial dating of in cave-deposited alluvium: unravelling long-term incision rates and complex speleogenesis in multi-level cave systems

2020 ◽  
Author(s):  
Gilles Rixhon ◽  
Didier L. Bourlès ◽  
Régis Braucher ◽  
Alexandre Peeters ◽  
Alain Demoulin
Keyword(s):  
Early Pleistocene ◽  
Middle Pleistocene ◽  
Fluvial Terrace ◽  
Base Level ◽  
Cave System ◽  
River Incision ◽  
Order Of Magnitude ◽  
History Of ◽  
Multi Level

&lt;p&gt;Multi-level cave systems record the history of regional river incision in abandoned alluvium-filled phreatic passages which, mimicking fluvial terrace sequences, represent former phases of fluvial base-level stability. In this respect, cosmogenic burial dating of in cave-deposited alluvium (usually via the nuclide pair &lt;sup&gt;26&lt;/sup&gt;Al/&lt;sup&gt;10&lt;/sup&gt;Be) represents a suitable method to quantify the pace of long-term river incision. Here, we present a dataset of fifteen &lt;sup&gt;26&lt;/sup&gt;Al/&lt;sup&gt;10&lt;/sup&gt;Be burial ages measured in fluvial pebbles washed into a multi-level cave system developed in Devonian limestone of the uplifted Ardenne massif (eastern Belgium). The large and well-documented Chawresse system is located along the lower Ourthe valley (i.e. the main Ardennian tributary of the Meuse river) and spans altogether an elevation difference exceeding 120 m.&lt;/p&gt;&lt;p&gt;The depleted &lt;sup&gt;26&lt;/sup&gt;Al/&lt;sup&gt;10&lt;/sup&gt;Be ratios measured in four individual caves show two main outcomes. Firstly, computed burial ages ranging from ~0.2 to 3.3 Ma allows highlighting an acceleration by almost one order of magnitude of the incision rates during the first half of the Middle Pleistocene (from ~25 to ~160 m/Ma). Secondly, according to the relative elevation above the present-day floodplain of the sampled material in the Manants cave (&lt;35 m), the four internally-consistent Early Pleistocene burial ages highlight an &amp;#8220;anomalous&amp;#8221; old speleogenesis in the framework of a gradual base-level lowering. They instead point to intra-karsting reworking of the sampled material in the topographically complex Manants cave. This in turn suggests an independent, long-lasting speleogenetic evolution of this specific cave, which differs from the &lt;em&gt;per descensum&lt;/em&gt; model of speleogenesis generally acknowledged for the regional multi-level cave systems and their abandoned phreatic galleries. In addition to its classical use for inferring long-term incision rates, cosmogenic burial dating can thus contribute to better understand specific and complex speleogenetic evolution.&lt;/p&gt;

scholarly journals Laporan Kasus: Manifestasi Oral Penderita Hipertensi berupa Ginggival Enlargement

2020 ◽  
Vol 17 (2) ◽  
pp. 54
Author(s):  
Anindita L. ◽  
Aris Aji K. ◽  
Arcadia Sulistijo J.
Keyword(s):  
Case Reports ◽  
Gingival Tissue ◽  
High Dose ◽  
Gingival Inflammation ◽  
Gingival Enlargement ◽  
History Of ◽  
Root Planning ◽  
Pro Inflammatory Cytokines

Hypertension presents an increase in blood pressure following the oral manifestations, such as gingival enlargement. A 42-year-old woman came to the General Sudirman University Dental and Oral Hospital complaining of enlarged front gums seven years ago. The patient had a history of hypertension and regularly consumed drugs, amlodipine 5 mg. Extraoral examination revealed no lymphadenopathy and no swelling of the head and neck area. Intraoral examination revealed a gingival enlargement involving the papilla to the gingival margin present on the entire upper and lower labial gingival surface. The patient's diagnosis was gingival enlargement caused by gingival enlargement due to the use of amlodipine. Gingival enlargement has been noted with long-term or high-dose amlodipine use. The mechanism of amlodipine in causing gingival enlargement is through the role of fibroblasts with abnormal susceptibility to the drug, resulting in increased levels of protein synthesis, especially collagen. The role of pro-inflammatory cytokines occurs through an increase in interleukin-1β (IL-1β) and IL-6 in the inflamed gingival tissue due to the gingival fibrogenic response to drugs. Therapies were DHE and scaling and root planning as phase I in periodontal treatment. Plaque elimination is vital to reduce gingival inflammation that may occur. Substitution of the drug amlodipine may be needed if there is no improvement. Based on case reports, hypertension patients who took amlodipine could have gingival enlargement. The therapy given was plaque elimination in the form of DHE and Scaling and regular check-ups with the dentist.

scholarly journals The crucial role of genome-wide genetic variation in conservation

2021 ◽  
Vol 118 (48) ◽  
pp. e2104642118
Author(s):  
Marty Kardos ◽  
Ellie E. Armstrong ◽  
Sarah W. Fitzpatrick ◽  
Samantha Hauser ◽  
Philip W. Hedrick ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Environmental Changes ◽  
Population Viability ◽  
Adaptive Potential ◽  
Biodiversity Crisis ◽  
Genome Wide ◽  
Simulation Based ◽  
Functional Genetic Variation

The unprecedented rate of extinction calls for efficient use of genetics to help conserve biodiversity. Several recent genomic and simulation-based studies have argued that the field of conservation biology has placed too much focus on conserving genome-wide genetic variation, and that the field should instead focus on managing the subset of functional genetic variation that is thought to affect fitness. Here, we critically evaluate the feasibility and likely benefits of this approach in conservation. We find that population genetics theory and empirical results show that conserving genome-wide genetic variation is generally the best approach to prevent inbreeding depression and loss of adaptive potential from driving populations toward extinction. Focusing conservation efforts on presumably functional genetic variation will only be feasible occasionally, often misleading, and counterproductive when prioritized over genome-wide genetic variation. Given the increasing rate of habitat loss and other environmental changes, failure to recognize the detrimental effects of lost genome-wide genetic variation on long-term population viability will only worsen the biodiversity crisis.

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