Categorizing Different Approaches to the Cosmological Constant Problem

We have found that proposals addressing the old cosmological constant problem come in various categories. The aim of this paper is to identify as many different, credible mechanisms as possible and to provide them with a code for future reference. We find that they all can be classified into five different schemes of which we indicate the advantages and drawbacks. Besides, we add a new approach based on a symmetry principle mapping real to imaginary spacetime.Comment: updated version, accepted for publicatio

Loneliness, cumulative inequality and social capital in later life: Two stories

The potential impact of cumulative inequality upon loneliness in later life is under-researched. This study applies Ferraro and Shippee’s axioms of cumulative inequality to the narratives of two Northern Irish older women, who completed semi-structured diary entries over a 16-week period, recording and reflecting on their social lives and their personal histories. The two women were subsequently interviewed on the basis of what they had recorded. These stories reveal how the life trajectories of these two individuals are influenced by the different experiential impact of bonding and bridging social capital. Despite similar life experiences, significant and substantial differences emerged in the women’s stories, relating to work life, social class, the restrictions of a caring role, and physical and mental health. These two narratives not only provide evidence of the impact of cumulative inequality on loneliness but also highlight the lifetime impact of socio-economic status and access to capital affecting older women’s vulnerability to loneliness

Epigenetically-Inherited Centromere and Neocentromere DNA Replicates Earliest in S-Phase

Eukaryotic centromeres are maintained at specific chromosomal sites over many generations. In the budding yeast Saccharomyces cerevisiae, centromeres are genetic elements defined by a DNA sequence that is both necessary and sufficient for function; whereas, in most other eukaryotes, centromeres are maintained by poorly characterized epigenetic mechanisms in which DNA has a less definitive role. Here we use the pathogenic yeast Candida albicans as a model organism to study the DNA replication properties of centromeric DNA. By determining the genome-wide replication timing program of the C. albicans genome, we discovered that each centromere is associated with a replication origin that is the first to fire on its respective chromosome. Importantly, epigenetic formation of new ectopic centromeres (neocentromeres) was accompanied by shifts in replication timing, such that a neocentromere became the first to replicate and became associated with origin recognition complex (ORC) components. Furthermore, changing the level of the centromere-specific histone H3 isoform led to a concomitant change in levels of ORC association with centromere regions, further supporting the idea that centromere proteins determine origin activity. Finally, analysis of centromere-associated DNA revealed a replication-dependent sequence pattern characteristic of constitutively active replication origins. This strand-biased pattern is conserved, together with centromere position, among related strains and species, in a manner independent of primary DNA sequence. Thus, inheritance of centromere position is correlated with a constitutively active origin of replication that fires at a distinct early time. We suggest a model in which the distinct timing of DNA replication serves as an epigenetic mechanism for the inheritance of centromere position

Comparative Genomics Reveals Two Novel RNAi Factors in Trypanosoma brucei and Provides Insight into the Core Machinery

The introduction ten years ago of RNA interference (RNAi) as a tool for molecular exploration in Trypanosoma brucei has led to a surge in our understanding of the pathogenesis and biology of this human parasite. In particular, a genome-wide RNAi screen has recently been combined with next-generation Illumina sequencing to expose catalogues of genes associated with loss of fitness in distinct developmental stages. At present, this technology is restricted to RNAi-positive protozoan parasites, which excludes T. cruzi, Leishmania major, and Plasmodium falciparum. Therefore, elucidating the mechanism of RNAi and identifying the essential components of the pathway is fundamental for improving RNAi efficiency in T. brucei and for transferring the RNAi tool to RNAi-deficient pathogens. Here we used comparative genomics of RNAi-positive and -negative trypanosomatid protozoans to identify the repertoire of factors in T. brucei. In addition to the previously characterized Argonaute 1 (AGO1) protein and the cytoplasmic and nuclear Dicers, TbDCL1 and TbDCL2, respectively, we identified the RNA Interference Factors 4 and 5 (TbRIF4 and TbRIF5). TbRIF4 is a 3′-5′ exonuclease of the DnaQ superfamily and plays a critical role in the conversion of duplex siRNAs to the single-stranded form, thus generating a TbAGO1-siRNA complex required for target-specific cleavage. TbRIF5 is essential for cytoplasmic RNAi and appears to act as a TbDCL1 cofactor. The availability of the core RNAi machinery in T. brucei provides a platform to gain mechanistic insights in this ancient eukaryote and to identify the minimal set of components required to reconstitute RNAi in RNAi-deficient parasites

Elevated plasma levels of cardiac troponin-I predict left ventricular systolic dysfunction in patients with myotonic dystrophy type 1:A multicentre cohort follow-up study

Objective: High sensitivity plasma cardiac troponin-I (cTnI) is emerging as a strong predictor of cardiac events in a variety of settings. We have explored its utility in patients with myotonic dystrophy type 1 (DM1). Methods: 117 patients with DM1 were recruited from routine outpatient clinics across three health boards. A single measurement of cTnI was made using the ARCHITECT STAT Troponin I assay. Demographic, ECG, echocardiographic and other clinical data were obtained from electronic medical records. Follow up was for a mean of 23 months. Results: Fifty five females and 62 males (mean age 47.7 years) were included. Complete data were available for ECG in 107, echocardiography in 53. Muscle Impairment Rating Scale score was recorded for all patients. A highly significant excess (p = 0.0007) of DM1 patients presented with cTnI levels greater than the 99th centile of the range usually observed in the general population (9 patients; 7.6%). Three patients with elevated troponin were found to have left ventricular systolic dysfunction (LVSD), compared with four of those with normal range cTnI (33.3% versus 3.7%; p = 0.001). Sixty two patients had a cTnI level < 5ng/L, of whom only one had documented evidence of LVSD. Elevated cTnI was not predictive of severe conduction abnormalities on ECG, or presence of a cardiac device, nor did cTnI level correlate with muscle strength expressed by Muscle Impairment Rating Scale score. Conclusions: Plasma cTnI is highly elevated in some ambulatory patients with DM1 and shows promise as a tool to aid cardiac risk stratification, possibly by detecting myocardial involvement. Further studies with larger patient numbers are warranted to assess its utility in this setting

Abrupt global events in the Earth's history: a physics perspective

The timeline of the Earth's history reveals quasi-periodicity of the geological record over the last 542 Myr, on timescales close, in the order of magnitude, to 1 Myr. What is the origin of this quasi-periodicity? What is the nature of the global events that define the boundaries of the geological time scale? I propose that a single mechanism is responsible for all three types of such events: mass extinctions, geomagnetic polarity reversals, and sea-level fluctuations. The mechanism is fast, and involves a significant energy release. The mechanism is unlikely to have astronomical causes, both because of the energies involved, and because it acts quasi-periodically. It must then be sought within the Earth itself. And it must be capable of reversing the Earth's magnetic field. The last requirement makes it incompatible with the consensus model of the origin of the geomagnetic field - the hydromagnetic dynamo operating in the Earth's fluid core. In the second part of the paper, I show that a vast amount of seemingly unconnected geophysical and geological data can be understood in a unified way if the source of the Earth's main magnetic field is a ~200-km-thick lithosphere, repeatedly magnetized as a result of methane-driven oceanic eruptions, which produce ocean flow capable of dynamo action. The eruptions are driven by the interplay of buoyancy forces and exsolution of dissolved gas, which accumulates in the oceanic water masses prone to stagnation and anoxia. Polarity reversals, mass extinctions, and sequence boundaries are consequences of these eruptions. Unlike the consensus model of geomagnetism, this scenario is consistent with the paleomagnetic data showing that "directional changes during a [geomagnetic polarity] reversal can be astonishingly fast, possibly occurring as a nearly instantaneous jump from one inclined dipolar state to another in the opposite hemisphere".Comment: Final journal version. New title, significant changes. Supersedes v.

Genomic Landscape of a Three-Generation Pedigree Segregating Affective Disorder

Bipolar disorder (BPD) is a common psychiatric illness with a complex mode of inheritance. Besides traditional linkage and association studies, which require large sample sizes, analysis of common and rare chromosomal copy number variants (CNVs) in extended families may provide novel insights into the genetic susceptibility of complex disorders. Using the Illumina HumanHap550 BeadChip with over 550,000 SNP markers, we genotyped 46 individuals in a three-generation Old Order Amish pedigree with 19 affected (16 BPD and three major depression) and 27 unaffected subjects. Using the PennCNV algorithm, we identified 50 CNV regions that ranged in size from 12 to 885 kb and encompassed at least 10 single nucleotide polymorphisms (SNPs). Of 19 well characterized CNV regions that were available for combined genotype-expression analysis 11 (58%) were associated with expression changes of genes within, partially within or near these CNV regions in fibroblasts or lymphoblastoid cell lines at a nominal P value <0.05. To further investigate the mode of inheritance of CNVs in the large pedigree, we analyzed a set of four CNVs, located at 6q27, 9q21.11, 12p13.31 and 15q11, all of which were enriched in subjects with affective disorders. We additionally show that these variants affect the expression of neuronal genes within or near the rearrangement. Our analysis suggests that family based studies of the combined effect of common and rare CNVs at many loci may represent a useful approach in the genetic analysis of disease susceptibility of mental disorders

A systematic review of the literature on digital transformation: insights and implications for strategy and organizational change

In this article we provide a systematic review of the extensive yet diverse and fragmented literature on digital transformation (DT), with the goal of clarifying boundary conditions to investigate the phenomenon from the perspective of organizational change. On the basis of 279 articles, we provide a multi-dimensional framework synthesizing what is known about DT and discern two important thematical patterns: DT is moving firms to malleable organizational designs that enable continuous adaptation, and this move is embedded in and driven by digital business ecosystems. From these two patterns, we derive four perspectives on the phenomenon of DT: technology impact, compartmentalized adaptation, systemic shift and holistic co-evolution. Linking our findings and interpretations to existing work, we find that the nature of DT is only partially covered by conventional frameworks on organizational change. On the basis of this analysis, we derive a research agenda and provide managerial implications for strategy and organizational change.info:eu-repo/semantics/publishedVersio