Hasil untuk "Evolution"

Katharina Kaltseis, Sarah Maier, Karin Zebenholzer et al.

Abstract Background Triptans are highly effective acute treatments for migraine attacks, yet population-level data suggest persistent underuse. Updated real-world data on triptan use and overuse in Austria are lacking. Methods This nationwide, retrospective claims-based study analysed triptan use and overuse in Austria in 2023. Adults (≥ 18 years) with at least one dispensed triptan were identified. Triptan overuse was defined as the dispensing of ≥ 30 defined daily doses (DDDs) in at least one quarter, consistent with the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria. Data on demographics, preventive migraine therapies, antidepressant use, sick leave, and hospital admissions were assessed and compared with data from 2007 using identical methodology. Results Among 7.75 million insured adults, 63,729 individuals (0.82%) fulfilled the inclusion criteria and used triptans, representing a 46% increase since 2007. However, this corresponds to an estimated number of approximately 8% of individuals with migraine. Triptan overuse more than doubled compared with 2007 (12.5% vs. 5.9%) and was associated with older age, with the largest proportion of overusers being 51–65 years old. Overusers showed substantially higher use of preventive therapies, including anti-calcitonin-gene-related-peptide (CGRP) antibodies (21.8% vs. 9.7%), and antidepressants (24.8% vs. 19.9%) (all p < 0.001). Hospital admissions were slightly more frequent among overusers, whereas sick-leave days were less frequent in this group. Women were more likely than men to use triptans, anti-CGRP antibodies, and antidepressants. Conclusion Despite increased triptan use over the past 15 years, overall utilization in Austria remains low, while the percentage of patients with triptan overuse has more than doubled. Preventive migraine therapies remain infrequently prescribed. Higher rates of hospital admissions and concomitant antidepressant use may indicate a greater overall disease burden among triptan overusers. Graphical Abstract

Lydia M. O’Sullivan, Clay J. Newton, Keith R. Underwood et al.

In the bison industry, both heifers and bulls are marketed and harvested at various ages, generally ranging from 20 to 30 months. Bulls represent the greatest proportion of the slaughter mix, as the bison industry does not routinely castrate, leaving males intact throughout the growing and finishing phase. This practice makes bulls available for use during the breeding season prior to the finishing phase. Therefore, the objective of this study was to evaluate the influence of bull age and use in the breeding herd on carcass characteristics, meat quality, and sensory characteristics of bison bulls. Grass-finished bison bulls were assigned to one of two finishing treatments: 1) Young bulls (n = 98) finished on fall pasture and harvested at 30 months of age with no exposure to the breeding herd, or 2) Mature bulls (n = 24) finished on early summer pasture and harvested at 36 months of age following use in the breeding herd. Bison were harvested, carcass data were recorded, and striploins were collected for the analysis of meat quality attributes. Mature bulls had greater hot carcass weight, ribeye area, kidney fat percentage, and marbling score compared to Young bulls. Objective tenderness was affected by the interaction of postmortem aging and finishing treatment. Steaks from Young bison bulls were more tender at all aging time points compared to steaks from Mature bison bulls. Variation in tenderness between treatment groups was likely not due to differences in collagen, as total collagen was greater in steaks from Young bulls. Consumer panelists rated steaks from Mature bulls higher for toughness intensity and flavor liking and lower for off-flavor intensity. Trained panelists rated steaks from Young bulls higher for flavor intensity, while ratings for toughness and juiciness were increased for Mature bulls. Collectively, results from this study indicate that bulls used in the breeding herd and marketed at 36 months of age produced heavier carcasses. However, Mature bulls were tougher at all postmortem aging days and required 21 days of aging to reach an acceptable level of tenderness, which was detected by both trained and consumer panelists.

Xuying Hu, Qian Zhang, Meiling Ge et al.

Deep-sea corals are critical to global exploration of deep-sea biodiversity, but research on them in the Indian Ocean is very limited. In this study, we report the first discovery of two new species of red corals at a depth of 1697 m in the western Indian Ocean. The species were identified through detailed morphological analysis, including microscopic examination of colony structure, branches and autozooids (assessing size, abundance and spacing), as well as scanning electron microscopy (SEM) of sclerite morphology and quantity. Two species for the genus Hemicorallium Gray, 1867 were found as new species, designated Hemicorallium indicodensum sp. nov. and Hemicorallium jiaolongensis sp. nov. H. indicodensum sp. nov. is characterised by densely branched structures and numerous globular double-club sclerites, distinguishing it from other species. Meanwhile, H. jiaolongensis sp. nov. features yellowish-white colonies with short rods with sharp, large radial projections in the tentacles. Four mitochondrial regions were used to reveal the phylogenetic relationship in Coralliidae, supporting the taxonomic placement of these two new species. This study provides significant new insights into the biodiversity of deep-sea corals in the Indian Ocean, enriching the known species pool. Additionally, a more comprehensive key to the genus Hemicorallium is provided, further enhancing our understanding of the group’s taxonomy.

Mario Valenti, Matteo Bianco, Alessandra Narcisi et al.

Actinic keratosis (AK) is a frequent precancerous skin lesion that mostly affects chronically sun-exposed areas. Chronic sun damage leads to various mutations in onco-suppressor and oncogenic genes which cause an uncontrolled proliferation of atypical keratinocytes. Untreated AKs may evolve in cutaneous squamous cell carcinoma (cSCC), with the consequent need for dermato-surgical excision or even for systemic immunotherapy in case of invasive/metastatic cSCCs. Epidemiology data on AK prevalence are various, however, the literature unanimously reports an increasing prevalence due to the aging of the population. Clinically AKs appear as a scaly, erythematous macule or papule or hyperkeratotic plaque. Management of AKs and the field of cancerization is important to avoid the natural evolution into squamous cell carcinomas (SCCs). Both physical and topical treatments are approved for managing AKs. Patient compliance with topical regimens is usually low due to the length of the posology and frequent skin adverse events. A recently approved tirbanibulin-based ointment, showed potential for inhibiting cell proliferation and blocking SRC-kinases, implicated in the progression of AKs in SCCs. The advantage of this new treatment is the practical posology, with a daily application for 5 consecutive days on AKs of the face-scalp area. Local skin reactions are usually mild and do not require treatment discontinuation. The short course of this new therapy and its excellent tolerance massively increased patient compliance. This article reviews what is currently known about this new therapy from its mechanism of action to clinical trial outcomes regarding safety, effectiveness, and patient adherence to the treatment.

Callum M Ives, Linh Nguyen, Carl A Fogarty et al.

Glycosylation of the SARS-CoV-2 spike (S) protein represents a key target for viral evolution because it affects both viral evasion and fitness. Successful variations in the glycan shield are difficult to achieve though, as protein glycosylation is also critical to folding and structural stability. Within this framework, the identification of glycosylation sites that are structurally dispensable can provide insight into the evolutionary mechanisms of the shield and inform immune surveillance. In this work, we show through over 45 μs of cumulative sampling from conventional and enhanced molecular dynamics (MD) simulations, how the structure of the immunodominant S receptor binding domain (RBD) is regulated by N-glycosylation at N343 and how this glycan’s structural role changes from WHu-1, alpha (B.1.1.7), and beta (B.1.351), to the delta (B.1.617.2), and omicron (BA.1 and BA.2.86) variants. More specifically, we find that the amphipathic nature of the N-glycan is instrumental to preserve the structural integrity of the RBD hydrophobic core and that loss of glycosylation at N343 triggers a specific and consistent conformational change. We show how this change allosterically regulates the conformation of the receptor binding motif (RBM) in the WHu-1, alpha, and beta RBDs, but not in the delta and omicron variants, due to mutations that reinforce the RBD architecture. In support of these findings, we show that the binding of the RBD to monosialylated ganglioside co-receptors is highly dependent on N343 glycosylation in the WHu-1, but not in the delta RBD, and that affinity changes significantly across VoCs. Ultimately, the molecular and functional insight we provide in this work reinforces our understanding of the role of glycosylation in protein structure and function and it also allows us to identify the structural constraints within which the glycosylation site at N343 can become a hotspot for mutations in the SARS-CoV-2 S glycan shield.

Huaiyuan Liu, Donglin Ma, Yantao Li et al.

When depositing films on a complex workpiece surface by magnetron sputtering, the shadow effect occurs and causes the columnar structure to tilt toward the substrate owing to the oblique incident angle of the plasma flux, affecting the microstructure and properties of the films. Improving the surface diffusion could alleviate the shadow effect, whereas changing the energy of the deposited particles could improve surface diffusion. Different substrate conductivities could affect the energy of the deposited particles when they reach the substrate. In this study, Si (semiconductor) and SiO₂ (insulator) sheets are mounted on the inner surface of a hemispherical workpiece, and Ti films with different thicknesses (adjusted by the deposition time) are deposited on the inner surface of the hemispherical workpiece by direct current magnetron sputtering. The results show that there is a threshold thickness and incident angle before the films are affected by the shadow effect. The threshold could be affected by the film thickness, the incident angle, and the conductivity of the substrate. The threshold would decrease as the film thickness or incidence angle increased or the conductivity of the substrate decreased. When the film thickness or incident angle does not reach the threshold, the film would not be affected by the shadow effect. In addition, the film deposited later would tilt the vertical columnar structure of the film deposited earlier. Owing to the different conductivities, the shadow effect manifest earlier for Ti films deposited on the insulator SiO₂ than for films deposited on the semiconductor Si when the film thickness is >500 nm.

Timothy Latim, Jonathan Kplorla Agbeh

This article presents two modernist building case studies, one each from East and West Africa which explore approaches to modernist public building conservation. The Rukurato Hall in East Africa, formerly used as a regional assembly hall for the Bunyoro Kingdom in Uganda, is now used as the parliament building of the Bunyoro Kitara Kingdom. The Great Hall in West Africa at the Kumasi University of Science and Technology (KNUST) serves as an institutional hall; it is a monument of academic and cultural significance in Kumasi. This article delves into the historical evolution of the Great Hall, which has hosted numerous essential events, ranging from local academic gatherings to distinguished international conferences since 1967. The Great Hall’s rich heritage and architectural prominence have been subject to various interventions aimed at conserving its essence. The examination of these interventions in maintaining the integrity of the building while adapting to the changing needs of the university underscores the delicate balance required between modernization and safeguarding cultural and architectural legacies. Both case studies present contrasting views on the challenges of conservation in the African context, resulting in different conservation efforts. In the case of the Rukurato Hall, arguable the loss of function for a significant period, before reinstatement in the late 1990s and challenges of funding have greatly influenced the ability to realize conservation ambitions. In the Great Hall, whilst conservation funds were secured, and the conservation effort was successful, the use of the Hall has been ‘controlled’ and various actions have arguably tested the authenticity of the conservation process transforming the building aesthetic in the process. This article employs methods of document analysis, archival research, and interviews with key stakeholders.

Jenny Greene, Rachel Bezanson, Masami Ouchi et al.

We present the Prime Focus Spectrograph (PFS) Galaxy Evolution pillar of the 360-night PFS Subaru Strategic Program. This 130-night program will capitalize on the wide wavelength coverage and massive multiplexing capabilities of PFS to study the evolution of typical galaxies from cosmic dawn to the present. From Lyman alpha emitters at z~7 to probe reionization, drop-outs at z~3 to map the inter-galactic medium in absorption, and a continuum-selected sample at z~1.5, we will chart the physics of galaxy evolution within the evolving cosmic web. This article is dedicated to the memory of Olivier Le Fevre, who was an early advocate for the construction of PFS, and a key early member of the Galaxy Evolution Working Group.

Kirana Widyastuti, Kirana Widyastuti, Romain Reuillon et al.

Agent-based models have been developed and widely employed to assess the impact of disturbances or conservation management on animal habitat use, population development, and viability. However, the direct impacts of canopy disturbance on the arboreal movement of individual primates have been less studied. Such impacts could shed light on the cascading effects of disturbances on animal health and fitness. Orangutans are an arboreal primate that commonly encounters habitat quality deterioration due to land-use changes and related disturbances such as forest fires. Forest disturbance may, therefore, create a complex stress scenario threatening orangutan populations. Due to forest disturbances, orangutans may adapt to employ more terrestrial, as opposed to arboreal, movements potentially prolonging the search for fruiting and nesting trees. In turn, this may lead to changes in daily activity patterns (i.e., time spent traveling, feeding, and resting) and available energy budget, potentially decreasing the orangutan's fitness. We developed the agent-based simulation model BORNEO (arBOReal aNimal movEment mOdel), which explicitly describes both orangutans' arboreal and terrestrial movement in a forest habitat, depending on distances between trees and canopy structures. Orangutans in the model perform activities with a motivation to balance energy intake and expenditure through locomotion. We tested the model using forest inventory data obtained in Sebangau National Park, Central Kalimantan, Indonesia. This allowed us to construct virtual forests with real characteristics including tree connectivity, thus creating the potential to expand the environmental settings for simulation experiments. In order to parameterize the energy related processes of the orangutans described in the model, we applied a computationally intensive evolutionary algorithm and evaluated the simulation results against observed behavioral patterns of orangutans. Both the simulated variability and proportion of activity budgets including feeding, resting, and traveling time for female and male orangutans confirmed the suitability of the model for its purpose. We used the calibrated model to compare the activity patterns and energy budgets of orangutans in both natural and disturbed forests . The results confirm field observations that orangutans in the disturbed forest are more likely to experience deficit energy balance due to traveling to the detriment of feeding time. Such imbalance is more pronounced in males than in females. The finding of a threshold of forest disturbances that affects a significant change in activity and energy budgets suggests potential threats to the orangutan population. Our study introduces the first agent-based model describing the arboreal movement of primates that can serve as a tool to investigate the direct impact of forest changes and disturbances on the behavior of species such as orangutans. Moreover, it demonstrates the suitability of high-performance computing to optimize the calibration of complex agent-based models describing animal behavior at a fine spatio-temporal scale (1-m and 1-s granularity).

Ciara Baines, Richard Meitern, Randel Kreitsberg et al.

Comparative studies of cancer-related genes allow us to gain novel information about the evolution and function of these genes, but also to understand cancer as a driving force in biological systems and species life histories. So far, comparative studies of cancer genes have focused on mammals. Here, we provide the first comparative study of cancer-related gene copy number variation in fish. As fish are evolutionarily older and genetically more diverse than mammals, their tumour suppression mechanisms should not only include most of the mammalian mechanisms, but also reveal novel (but potentially phylogenetically older) previously undetected mechanisms. We have matched the sequenced genomes of 65 fish species from the Ensemble database with the cancer gene information from the COSMIC database. By calculating the number of gene copies across species using the Ensembl CAFE data (providing species trees for gene copy number counts), we were able to develop a novel, less resource demanding method for ortholog identification. Our analysis demonstrates a masked relationship with cancer-related gene copy number variation (CNV) and maximum lifespan in fish species, suggesting that higher tumour suppressor gene CNV lengthens and oncogene CNV shortens lifespan, when both traits are added to the model. Based on the correlation between tumour suppressor and oncogene CNV, we were able to show which species have more tumour suppressors in relation to oncogenes. It could therefore be suggested that these species have stronger genetic defences against oncogenic processes. Fish studies could yet be a largely unexplored treasure trove for understanding the evolution and ecology of cancer, by providing novel insights into the study of cancer and tumour suppression, in addition to the study of fish evolution, life-history trade-offs, and ecology.

Matteo Bisardi, Juan Rodriguez-Rivas, Francesco Zamponi et al.

During their evolution, proteins explore sequence space via an interplay between random mutations and phenotypic selection. Here we build upon recent progress in reconstructing data-driven fitness landscapes for families of homologous proteins, to propose stochastic models of experimental protein evolution. These models predict quantitatively important features of experimentally evolved sequence libraries, like fitness distributions and position-specific mutational spectra. They also allow us to efficiently simulate sequence libraries for a vast array of combinations of experimental parameters like sequence divergence, selection strength and library size. We showcase the potential of the approach in re-analyzing two recent experiments to determine protein structure from signals of epistasis emerging in experimental sequence libraries. To be detectable, these signals require sufficiently large and sufficiently diverged libraries. Our modeling framework offers a quantitative explanation for the variable success of recently published experiments. Furthermore, we can forecast the outcome of time- and resource-intensive evolution experiments, opening thereby a way to computationally optimize experimental protocols.

Daniel G. Boyce, Brian Petrie, Kenneth T. Frank

Abstract Since 1960, landings of Atlantic herring have been the greatest of any marine species in Canada, surpassing Atlantic cod and accounting for 24% of the total seafood harvested in Atlantic Canada. The Scotian Shelf‐Bay of Fundy herring fisheries (NAFO Division 4VWX) is among Canada's oldest and drives this productivity, accounting for up to 75% of the total herring catch in some years. The stocks’ productivity and overall health have declined since 1965. Despite management measures to promote recovery implemented since 2003, biomass remains low and is declining. The factors that drive the productivity of 4VWX herring are primarily unresolved, likely impeding the effectiveness of management actions on this stock. We evaluated potential drivers of herring variability by analyzing 52 time‐series that describe the temporal and spatial evolution of the 4VWX herring population and the physical, ecological, and anthropogenic factors that could affect them using structural equation models. Variation in herring biomass was best accounted for by the exploitation rate's negative effect and the geographic distribution of fishing and recruitment. Thermal phenology and temperature adversely and egg predation positively impacted the early life stage mortality rate and, ultimately, adult biomass. These findings are broadly relevant to fisheries management, but particularly for 4VWX herring, where the current management approach does not consider their early life stage dynamics or assess them within the ecosystem or climate change contexts.

Abdulkadir Kose, Haeyoung Lee, Chuan Heng Foh et al.

It is envisaged that 5G can enable many vehicular use cases that require high capacity, ultra-low latency and high reliability. To support this, 5G proposes the use of dense small cells technology as well as and highly directional mmWave systems deployment, among many other new advanced communication technologies, to boost the network capacity, reduce latency and provide high reliability. In such systems, enabling vehicular communication, where the nodes are highly mobile, requires robust mobility management techniques to minimise signalling cost and interruptions during frequent handovers. This presents a major challenge that communication system engineers need to address to realise the promise of 5G systems for V2X and similar applications. In this paper, we provide an overview of recent progresses in the development of handover and beam management techniques in 5G communication systems. We conduct a critical appraisal of current research on beam level and cell level mobility management in 5G mmWave networks considering the ultra-reliable and low-latency communication requirements within the context of V2X applications. We also provide an insight into the open challenges and the emerging trends as well as the possible evolution beyond the horizon of 5G.

Ina Krause

This paper analyzes how the organization of work has changed since the 1990s including the emergence of digital forms of employment. Following the evolution of work over the course of the 20th century and the start of the 21st, this paper is divided into three sections: the adoption of industrialization, automation and digitalization, and, finally, the virtual economy. Each of these periods correspond with a certain model of production: Fordism, Taylorism, and Uberism (or Waymoism, named for Google’s Waymo project), which lie at the basis of the organization of work (process management, project management, and joint or cooperative activity) and present different sets of skill requirements. During the discussion of the evolution of work organization, including its geographical and temporal aspects, how attitudes of the individuals towards work have changed over time is discussed. Finally, the concept of coworking is analyzed as it forms the cultural foundation for virtual work. Due to the continuing nature of this research, this article presents only the initial results. This paper aims to determine how coworking spaces impact the socioeconomic development of emerging and developed regions. Fourteen in-depth interviews with managers of coworking spaces in a variety of regions serves as the empirical basis of this research over the course of periods of one and two months.

Igor Alekseevich Makarov, Anna Konstantinovna Sokolova

This paper examines the changing patterns of transnational value chains in the Asia-Pacific region. The methodology is based on the analysis of data extracted from the OECD – WTO Trade in Value Added Database (2016). The study demonstrates that 1) Asia-Pacific countries show extremely high involvement in the global value chains; 2) intra-Asian value chains develop at a fast pace, reflecting the trend towards regiona-lization of economic ties in Asia-Pacific (caused by the processes of transformation within China, the growing income divergence in the region and the development of regional integration mechanisms); 3) the level of participation in global value chains differs across countries and is subject to constant changes. In particular, Chinese manufacturers are moving to the processes with higher value added, and the role of an ‘assembly shop’ in the region is shifting to the ASEAN countries. Russia’s participation in the value chains in the Asia-Pacific region is currently limited to its role as a supplier of raw materials. High tariffs make manufacturing oriented towards Asia less viable, especially considering that most of Asia-Pacific countries have free trade agreements with each other. However, favorable rules of origin in Asian RTAs as well as good political relations with leading Asian countries in conditions of tensions between them still create some opportunities for involving Russia in regional value chains at the more advanced stages

Cathrine E. Fagernes, Kåre-Olav Stensløkken, Åsmund K. Røhr et al.

Abstract Without oxygen, most vertebrates die within minutes as they cannot meet cellular energy demands with anaerobic metabolism. However, fish of the genus Carassius (crucian carp and goldfish) have evolved a specialized metabolic system that allows them to survive prolonged periods without oxygen by producing ethanol as their metabolic end-product. Here we show that this has been made possible by the evolution of a pyruvate decarboxylase, analogous to that in brewer’s yeast and the first described in vertebrates, in addition to a specialized alcohol dehydrogenase. Whole-genome duplication events have provided additional gene copies of the pyruvate dehydrogenase multienzyme complex that have evolved into a pyruvate decarboxylase, while other copies retained the essential function of the parent enzymes. We reveal the key molecular substitution in duplicated pyruvate dehydrogenase genes that underpins one of the most extreme hypoxic survival strategies among vertebrates and that is highly deleterious in humans.

Sundar Kunwar, Puran Pandey, Mao Sui et al.

Abstract Si-based optoelectronic devices embedded with metallic nanoparticles (NPs) have demonstrated the NP shape, size, spacing, and crystallinity dependent on light absorption and emission induced by the localized surface plasmon resonance. In this work, we demonstrate various sizes and configurations of palladium (Pd) nanostructures on Si (111) by the systematic thermal annealing with the variation of Pd thickness and annealing temperature. The evolution of Pd nanostructures are systematically controlled by the dewetting of thin film by means of the surface diffusion in conjunction with the surface and interface energy minimization and Volmer-Weber growth model. Depending on the control of deposition amount ranging between 0.5 and 100 nm at various annealing temperatures, four distinctive regimes of Pd nanostructures are demonstrated: (i) small pits and grain formation, (ii) nucleation and growth of NPs, (iii) lateral evolution of NPs, and (iv) merged nanostructures. In addition, by the control of annealing between 300 and 800 °C, the Pd nanostructures show the evolution of small pits and grains, isolated NPs, and finally, Pd NP-assisted nanohole formation along with the Si decomposition and Pd-Si inter-diffusion. The Raman analysis showed the discrepancies on phonon modes of Si (111) such that the decreased peak intensity with left shift after the fabrication of Pd nanostructures. Furthermore, the UV-VIS-NIR reflectance spectra revealed the existence of surface morphology dependent on absorption, scattering, and reflectance properties.

Diego Salvadori

In this article we present the database Dove/nondove, which aims aims to collect and list the texts of female authors who’ve wrote about places and spaces. The goal is to create a global hypertext, monitoring the evolution of specific themes (landscape and environment, pollution and ecological crisis, human non-human relation) in the Feminine literature.

Michael Golden, Eduardo García-Portugués, Michael Sørensen et al.

Recently described stochastic models of protein evolution have demonstrated that the inclusion of structural information in addition to amino acid sequences leads to a more reliable estimation of evolutionary parameters. We present a generative, evolutionary model of protein structure and sequence that is valid on a local length scale. The model concerns the local dependencies between sequence and structure evolution in a pair of homologous proteins. The evolutionary trajectory between the two structures in the protein pair is treated as a random walk in dihedral angle space, which is modelled using a novel angular diffusion process on the two-dimensional torus. Coupling sequence and structure evolution in our model allows for modelling both "smooth" conformational changes and "catastrophic" conformational jumps, conditioned on the amino acid changes. The model has interpretable parameters and is comparatively more realistic than previous stochastic models, providing new insights into the relationship between sequence and structure evolution. For example, using the trained model we were able to identify an apparent sequence-structure evolutionary motif present in a large number of homologous protein pairs. The generative nature of our model enables us to evaluate its validity and its ability to simulate aspects of protein evolution conditioned on an amino acid sequence, a related amino acid sequence, a related structure or any combination thereof.

Ananthu James, Kavita Jain

Although mutations drive the evolutionary process, the rates at which the mutations occur are themselves subject to evolutionary forces. Our purpose here is to understand the role of selection and random genetic drift in the evolution of mutation rates, and we address this question in asexual populations at mutation-selection equilibrium neglecting selective sweeps. Using a multitype branching process, we calculate the fixation probability of a rare nonmutator in a large asexual population of mutators, and find that a nonmutator is more likely to fix when the deleterious mutation rate of the mutator population is high. Compensatory mutations in the mutator population are found to decrease the fixation probability of a nonmutator when the selection coefficient is large. But, surprisingly, the fixation probability changes nonmonotonically with increasing compensatory mutation rate when the selection is mild. Using these results for the fixation probability and a drift-barrier argument, we find a novel relationship between the mutation rates and the population size. We also discuss the time to fix the nonmutator in an adapted population of asexual mutators, and compare our results with experiments.