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Avoiding chromosome pathology when replication forks collide
This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2013 Macmillan Publishers Limited.Chromosome duplication normally initiates through the assembly of replication fork complexes at defined origins1, 2. DNA synthesis by any one fork is thought to cease when it meets another travelling in the opposite direction, at which stage the replication machinery may simply dissociate before the nascent strands are finally ligated. But what actually happens is not clear. Here we present evidence consistent with the idea that every fork collision has the potential to threaten genomic integrity. In Escherichia coli this threat is kept at bay by RecG DNA translocase3 and by single-strand DNA exonucleases. Without RecG, replication initiates where forks meet through a replisome assembly mechanism normally associated with fork repair, replication restart and recombination4, 5, establishing new forks with the potential to sustain cell growth and division without an active origin. This potential is realized when roadblocks to fork progression are reduced or eliminated. It relies on the chromosome being circular, reinforcing the idea that replication initiation is triggered repeatedly by fork collision. The results reported raise the question of whether replication fork collisions have pathogenic potential for organisms that exploit several origins to replicate each chromosome.THe MRC, the Leverhulme Trust, and the BBSRC
Are acceptance and mindfulnessâbased interventions âvalue for moneyâ? Evidence from a systematic literature review
Objectives Acceptance and mindfulnessâbased interventions (A/MBIs) are recommended for people with mental health conditions. Although there is a growing evidence base supporting the effectiveness of different A/MBIs for mental health conditions, the economic case for these interventions has not been fully explored. The aim of this systematic review was to identify and appraise all available economic evidence of A/MBIs for the management of mental health conditions. Methods Eight electronic bibliographic databases (MEDLINE, MEDLINE InâProcess & Other NonâIndexed Citations, EMBASE, Web of Science, NHS Economic Evaluation Database (EED), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA) database, and EconLit) were searched for relevant economic evaluations published from each database's inception date until November 2017. Study selection, quality assessment, and data extraction were carried out according to published guidelines. Results Ten relevant economic evaluations presented in 11 papers were identified. Seven of the included studies were full economic evaluations (i.e., costs and effects assessed), and three studies were partial economic evaluations (i.e., only costs were considered in the analysis). The A/MBIs that had been subjected to economic evaluation were acceptance and commitment therapy (ACT), dialectical behaviour therapy (DBT), mindfulnessâbased cognitive therapy (MBCT), and mindfulnessâbased stress reduction (MBSR). In terms of clinical presentations, the evaluation of costâeffectiveness of A/MBIs has been more focused on depression and emotional unstable personality disorder with three and four economic evaluations, respectively. Three out of seven full economic evaluations observed that A/MBIs were costâeffective for the management of mental health conditions. Nevertheless, the heterogeneity of included populations, interventions, and economic evaluation study types limits the extent to which firm conclusions can currently be made. Conclusion This first substantive review of economic evaluations of A/MBIs indicates that more research is needed before firm conclusions can be reached on the costâeffectiveness of A/MBIs for mental health conditions. Practitioner points The findings of the review provide information that may be relevant to mental health service commissioners and decisionâmakers as all economic evidence available on acceptance and mindfulnessâbased interventions for mental health conditions is summarized. Evidence relating to the costâeffectiveness and costâsaving potential of acceptance and mindfulnessâbased interventions is focused mainly on depression and emotional unstable personality disorder to date. Heterogeneity in the specific forms of acceptance and mindfulnessâbased interventions may limit generalizability of the findings. The number of health economic evaluations relating to acceptance and mindfulnessâbased interventions remains relatively small. Further research in this area is required
Muscle coâactivation across activities of daily living in individuals with knee osteoarthritis
Neo-Aristotelian Naturalism and the Evolutionary Objection: Rethinking the Relevance of Empirical Science
Neo-Aristotelian metaethical naturalism is a modern attempt at naturalizing ethics using ideas from Aristotleâs teleological metaphysics. Proponents of this view argue that moral virtue in human beings is an instance of natural goodness, a kind of goodness supposedly also found in the realm of non-human living things. Many critics question whether neo-Aristotelian naturalism is tenable in light of modern evolutionary biology. Two influential lines of objection have appealed to an evolutionary understanding of human nature and natural teleology to argue against this view. In this paper, I offer a reconstruction of these two seemingly different lines of objection as raising instances of the same dilemma, giving neo-Aristotelians a choice between contradicting our considered moral judgment and abandoning metaethical naturalism. I argue that resolving the dilemma requires showing a particular kind of continuity between the norms of moral virtue and norms that are necessary for understanding non-human living things. I also argue that in order to show such a continuity, neo-Aristotelians need to revise the relationship they adopt with empirical science and acknowledge that the latter is relevant to assessing their central commitments regarding living things. Finally, I argue that to move this debate forward, both neo-Aristotelians and their critics should pay attention to recent work on the concept of organism in evolutionary and developmental biology
Chromosomal over-replication in Escherichia coli recG cells is triggered by replication fork fusion and amplified if replichore symmetry is disturbed
Chromosome duplication initiates via the assembly of replication forks at defined origins. Forks proceed in opposite directions until they fuse with a converging fork. Recent work highlights that fork fusions are highly choreographed both in pro- and eukaryotic cells. The circular Escherichia coli chromosome is replicated from a single origin (oriC), and a single fork fusion takes place in a specialised termination area opposite oriC that establishes a fork trap mediated by Tus protein bound at ter sequences that allows forks to enter but not leave. Here we further define the molecular details of fork fusions and the role of RecG helicase in replication termination. Our data support the idea that fork fusions have the potential to trigger local re-replication of the already replicated DNA. In ÎrecG cells this potential is realised in a substantial fraction of cells and is dramatically elevated when one fork is trapped for some time before the converging fork arrives. They also support the idea that the termination area evolved to contain such over-replication and we propose that the stable arrest of replication forks at ter/Tus complexes is an important feature that limits the likelihood of problems arising as replication terminates
A viscoelastic deadly fluid in carnivorous pitcher plants
Background : The carnivorous plants of the genus Nepenthes, widely
distributed in the Asian tropics, rely mostly on nutrients derived from
arthropods trapped in their pitcher-shaped leaves and digested by their
enzymatic fluid. The genus exhibits a great diversity of prey and pitcher forms
and its mechanism of trapping has long intrigued scientists. The slippery inner
surfaces of the pitchers, which can be waxy or highly wettable, have so far
been considered as the key trapping devices. However, the occurrence of species
lacking such epidermal specializations but still effective at trapping insects
suggests the possible implication of other mechanisms. Methodology/Principal
Findings : Using a combination of insect bioassays, high-speed video and
rheological measurements, we show that the digestive fluid of Nepenthes
rafflesiana is highly viscoelastic and that this physical property is crucial
for the retention of insects in its traps. Trapping efficiency is shown to
remain strong even when the fluid is highly diluted by water, as long as the
elastic relaxation time of the fluid is higher than the typical time scale of
insect movements. Conclusions/Significance : This finding challenges the common
classification of Nepenthes pitchers as simple passive traps and is of great
adaptive significance for these tropical plants, which are often submitted to
high rainfalls and variations in fluid concentration. The viscoelastic trap
constitutes a cryptic but potentially widespread adaptation of Nepenthes
species and could be a homologous trait shared through common ancestry with the
sundew (Drosera) flypaper plants. Such large production of a highly
viscoelastic biopolymer fluid in permanent pools is nevertheless unique in the
plant kingdom and suggests novel applications for pest control
A teleofunctional account of evolutionary mismatch.
This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s10539-016-9527-1When the environment in which an organism lives deviates in some essential way from that to which it is adapted, this is described as "evolutionary mismatch," or "evolutionary novelty." The notion of mismatch plays an important role, explicitly or implicitly, in evolution-informed cognitive psychology, clinical psychology, and medicine. The evolutionary novelty of our contemporary environment is thought to have significant implications for our health and well-being. However, scientists have generally been working without a clear definition of mismatch. This paper defines mismatch as deviations in the environment that render biological traits unable, or impaired in their ability, to produce their selected effects (i.e., to perform their proper functions in Neander's sense). The machinery developed by Millikan in connection with her account of proper function, and with her related teleosemantic account of representation, is used to identify four major types, and several subtypes, of evolutionary mismatch. While the taxonomy offered here does not in itself resolve any scientific debates, the hope is that it can be used to better formulate empirical hypotheses concerning the effects of mismatch. To illustrate, it is used to show that the controversial hypothesis that general intelligence evolved as an adaptation to handle evolutionary novelty can, contra some critics, be formulated in a conceptually coherent way
Effects of Antiepileptic Drugs on GABA Responses and on Reduction of GABA Responses by PTZ and DMCM on Mouse Neurons in Cell Culture
The mechanisms of action of antiepileptic drugs effective against generalized absence seizures (antiabsence AEDs) remain uncertain. Antiabsence AEDs are generally effective against seizures induced in experimental animals by pentylenĂtĂtrazol (PTZ) and methyl-6,7-dimethoxy-4-ethyl-Î-carboline-3-carboxylate (DMCM), drugs which reduce GABAergic inhibition. Thus, antiabsence AEDs have been suggested to enhance GABAergic inhibition. We studied the effects of several AEDs on GABA responses recorded from mouse spinal cord neurons grown in primary dissociated cell culture. Four antiabsence AEDs were included: ethosuximide (ESM), dimethadione (DMO), sodium valproate (VPA), and diazepam (DZP). Two experimental AEDs, CGS 9896 and ZK 91296, with anticonvulsant action against PTZ- or DMCM-induced seizures were also included. Possible effects of the antiabsence and experimental AEDS on PTZ- and DMCM-induced inhibition of GABA responses were also evaluated. PTZ and DMCM revers-ibly reduced GABA responses in a concentration-dependent manner. PTZ complĂtĂly inhibited GABA responses at 10 mM (IC 50 of 1.1 mM), whereas DMCM-induced inhibition of GABA responses reached a plateau level of 39% of control values at 1 p.M (IC 50 of 33 nM). ESM (1,200 ÎM), DMO (6 mM), VPA (200 u.M), CGS 9896 (2 ÎM), and ZK 98% (2 Î M ) did not alter GABA responses. DZP enhanced GABA responses in a concentration-dependent manner. The inhibition of GABA responses produced by PTZ 1 mM was unaltered by ESM (600 Î M ), DMO (6 mM), CGS 9896 (1 Î M), or ZK 9896 (1 ÎM)- Coapplication of VPA (200 ÎM) and PTZ (1 mM) slightly enhanced the PTZ effect. DZP (> 10 nM), however, reversed the PTZ-induced reduction of GABA responses. The DMCM (250 nM) inhibition of GABA-responses was unaltered by ESM (600 Î.M), DMO (2 mM), or VPA (200 ÎM). CGS 9896 (2 Î M ) and ZK 91296 (2 ÎM), however, antagonized the DMCM effect. DZP (> 10 nM) significantly reversed the DMCM-induced inhibition of GABA responses. The lack of effect of VPA, ESM, and DMO on postsynaptic GABA responses suggests that direct enhancement of postsynaptic GABA action is not a common mechanism of action of antiabsence AEDs. The AEDs DZP, CGS 98%, and ZK 912% all reversed DMCM, but not PTZ, reduction of GABA responses, suggesting that these AEDs blocked DMCM seizures by acting at benzodiazepine receptors. However, since only DZP enhanced GABA responses, it is unclear how CGS 98% and ZK 912% blocked PTZ seizures. Key Words: AnticonvulsantsâGABAâNeuron cultureâCell cultureâSpinal cord neuronsâConvulsants. RESUMEN Los mecanismos de accidn de las medicaciones antiepilĂpticas eficaces contra los ataques generalizados de ausencia (AEDs antiausencia) permanecen inciertos. Los AEDs antiausencia son, generalmente, eficaces contra ataques experimentales inducidos por el pentilentetrazol (PTZ) y el metil-6,7-dimetoxy-4-etil-Pcarbolina-3-carboxilato (DMCM) en animates, medicaciones que reducen la inhibiciĂn GABAĂrgica. Hemos estudiado los efectos de varios AEDs sobre respuestas-GABA registradas en las neuronas de la mĂdula espinal de ratones que habian crecido en cultivos de cĂlulas primarieas disociadas. Cuatro AEDs antiausencia fueron incluidos: etoxusimida (ESM), dimetadiona (DMO), valproato sĂdico (VPA) y diazepan (DZP). TambtĂn se incluyeron dos AEDs experimentales, CGS 9896 y ZK 912%, con acciĂn anticonvulsiva contra los ataques inducidos por PTZ o DMCM. TambiĂn se valoraron los posibles efectos de los AEDs antiausencia y experimentales sobre el PTZ y la inhibiciĂn de las respuestas-GABA inducidas por el DMCM. El PTZ y el DMCM redujeron las respuestas-GABA de modo reversible y dependiendo de sus concentraciones. El PTZ inhibiĂ cmpleta-mente las respuestas-GABA a 10 mM (IC 50 de 1.1 mM) mientras que la inhibitiĂn de las respuestas GABA inducida por el DMCM alcanzĂ un nivel estable del 39% de los valores control con 1 Î. M (IC 50 de 33 mM). La ESM (1200 Î.M), la DMO (6 mM), el VPA (200 Î M ), el CGS 98% (2 Î M) y el ZK 98% (2 Î M) no alteraron las respuestas-GABA. El DZP aumentĂ las respuestas GABA de una manera concentraciĂn-dependiente. La inhibition de las respuestas-GABA producidas por el PTZ (1 mM), no se altero con las ESM (600 Î M), la DMO (6 mM), el CGS 98% (1 Î M) o el ZK 98% (1 Î .M). La co-aplicacion de VPA (200 Î M) y el PTZ (1 mM) aument6 ligeramente los efectos del PTZ. Sin embargo el DZP (10 nM) revirtiĂ significativamente la inhibition de las respuestas GABA inducidas por el DMCM. La falta de efectos de CPA, ESM y DMO sobre las respuestas GABA post-sinĂpticas sugiere que el incremento de la acciĂn GABA post-sinĂptica no es un mecanismo comĂn de actuatiĂn de las AEDs antiausencia. Todas las AEDs DZP, CGS 98% y ZK 912% revirtieron la reduction de las respuestas GABA producidas por el DMCM pero no las inducidas por el PTZ lo que sugiere que estos AEDs bloquean los ataques DMCM actuando sobre los receptores de la benzodiazepina. Sin embargo, puesto que el incremento de las respuestas GABA sĂlĂ se produce por el DZP, permanece todavia sin aclarar el por quĂ el CGS 98% y el ZK 912% bloquean los ataques producidos por el PTZ. ZUSAMMENFASSUNG Der Wirkmechansimus von Antiepileptika gegen generalisierte Absencen ist unklar. Antiabsencemittel sind generell wirkungs-voll gegen PTZ- und Methyl-6,7-Dimethoxy-4-Ăthyl-P-Carbolin-Î-Carboxylat (DMCM) induzierte tierexperimentelle AnfĂlle, also von Medikamenten, die die GABA-erge Inhibition reduzieren. Es wurde vermutet, daĂ Antiabsencemittel die GABA-erge Inhibition verstĂrken. Wir untersuchten die Wirkung von verschiedenen Antiepileptika auf GABA-Antworten in spinalen MĂuseneuronen, die in Zellkulturen gew-achsen waren. Es wurden 4 Absencemittel untersucht: Ethosux-imid (ESM), Dimethadion (DMD), Sodium Valproat (VPA) und Diazepam (DZP). ZusĂtzlich wurden 2 experimentelle Antiepileptika, CGS 98% und ZK 912%, die gegen PTZ0 oder DMCM-induzierte AnfĂlle wirkungsvoll sind, eingeschlossen. Mogliche Wirkungen der Antiabsence- und experimentellen Antiepileptika auf PTZ- und DMCM-induzierte Hemmung der GABA-Antworten wurden ebenfalls ausgewertet. PTZ und DMCM zeigten eine konzentrationsabhĂngige reversible Reduktion der GABA-Antworten. PTZ zeigte eine komplette Hemmung der GABA-Antworten bei 10 mM (IC 50 1,1 mM), DMCM-Hemmung der GABA-Antworten zeigte ein Plateau von 39% der Kontroll-werte bei 1 uJtf (ICJO von 33 mAfl. ESM (1200 uJtf), DMD (6 mM), VPA (200 Î M), CGS 98% (2 Î M) und ZK 98% (2 Î M) anderten nicht die GABA-Antworten. DZP verstarkte die GABA-Antworten konzentrationsabhangig. Die durch PTZ (1 mM) hervorgerufene Hemmung der GABA-Antworten war bei ESM (600 Î M), DMD (6 mM), CGS 98% (1 mAO und ZK 3836 (1 mM) unverĂndert. ZusĂtliche Anwendung von VPA (200 mM) und PTZ (1 mM) verstĂrkten geringfĂgig den PTZ-Effekt. DZP (10 nM) kehrte die durch PTZ hervorgerufene Reduktion der GABA-Antworten um. Die durch DMCM (250 nM) hervorgerufene Hemmung der GABA-Antworten war durch ESM (600 Î .M), DMD (2 mM) und VPA (200 Î M ) unbeeinflusst. CGS 98% (2 Î M) und ZK 912% (2 Î M ) antagonisierten die DMCM-Wirkung. DZP (>10 nM) kehrte die durch DMCM-induzierte Hemmung der GABA-Antworten um. Das Fehlen einer Wirkung von VPA. ESM und DMD auf die postsynaptischen GABA-Antworten legen nahe, daĂ eine direkte VerstĂrkung der postsynaptischen GABA-Aktion kein gemeinsamer Mechanis-mus der Antiabsencemittel darstellt. Die Antiepileptika DZP, CGS 98% und ZK 912% kehrten die DMCM-Wirkung auf die GABA-Antworten um, jedoch nicht die von PTZ, was vermuten lapt, daĂ diese Antiepileptika die DMCM-AnfĂlle Ăber die Wirkung an den Benzodiazipin-Rezeptoren verhinderte. Da jedoch nur DZP GABA-Antworten verstarkte, ist unklar, in welcher Weise CGS 98% und ZK 912% die PTZ-AnfaUe ver-hinderten.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65188/1/j.1528-1157.1989.tb05275.x.pd
Glucosylsphingosine Is a Highly Sensitive and Specific Biomarker for Primary Diagnostic and Follow-Up Monitoring in Gaucher Disease in a Non-Jewish, Caucasian Cohort of Gaucher Disease Patients
Gaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient ÎČ-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments.Here, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs).Only GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine.In summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD
ruvA Mutants that resolve Holliday junctions but do not reverse replication forks
RuvAB and RuvABC complexes catalyze branch migration and resolution of Holliday junctions (HJs) respectively. In addition to their action in the last steps of homologous recombination, they process HJs made by replication fork reversal, a reaction which occurs at inactivated replication forks by the annealing of blocked leading and lagging strand ends. RuvAB was recently proposed to bind replication forks and directly catalyze their conversion into HJs. We report here the isolation and characterization of two separation-of-function ruvA mutants that resolve HJs, based on their capacity to promote conjugational recombination and recombinational repair of UV and mitomycin C lesions, but have lost the capacity to reverse forks. In vivo and in vitro evidence indicate that the ruvA mutations affect DNA binding and the stimulation of RuvB helicase activity. This work shows that RuvA's actions at forks and at HJs can be genetically separated, and that RuvA mutants compromised for fork reversal remain fully capable of homologous recombination
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