Smc5/6 coordinates formation and resolution of joint molecules with chromosome morphology to ensure meiotic divisions

During meiosis, Structural Maintenance of Chromosome (SMC) complexes underpin two fundamental features of meiosis: homologous recombination and chromosome segregation. While meiotic functions of the cohesin and condensin complexes have been delineated, the role of the third SMC complex, Smc5/6, remains enigmatic. Here we identify specific, essential meiotic functions for the Smc5/6 complex in homologous recombination and the regulation of cohesin. We show that Smc5/6 is enriched at centromeres and cohesin-association sites where it regulates sister-chromatid cohesion and the timely removal of cohesin from chromosomal arms, respectively. Smc5/6 also localizes to recombination hotspots, where it promotes normal formation and resolution of a subset of joint-molecule intermediates. In this regard, Smc5/6 functions independently of the major crossover pathway defined by the MutLγ complex. Furthermore, we show that Smc5/6 is required for stable chromosomal localization of the XPF-family endonuclease, Mus81-Mms4Eme1. Our data suggest that the Smc5/6 complex is required for specific recombination and chromosomal processes throughout meiosis and that in its absence, attempts at cell division with unresolved joint molecules and residual cohesin lead to severe recombination-induced meiotic catastroph

A Bayesian re-assessment of two Phase II trials of gemcitabine in metastatic nasopharyngeal cancer

The Simon two-stage minimax design is a popular statistical design used in Phase II clinical trials. The analysis of the data arising from the design typically involves the use of frequentist statistics. This paper presents an alternative, Bayesian, approach to the design and analysis of Phase II clinical trials. In particular, we consider how a Bayesian approach could have affected the design, analysis and interpretation of two parallel Phase II trials of the National Cancer Centre Singapore, on the activity of gemcitabine in chemotherapy-naïve and in previously treated patients with metastatic nasopharyngeal carcinoma. We begin by explaining the Bayesian methodology and contrasting it with the frequentist approach. We then carry out a Bayesian analysis of the trial results. The conclusions drawn using the Bayesian approach were in general agreement with those obtained from the frequentist analysis. However they had the advantage of allowing for different and potentially more useful interpretations to be made regarding the trial results, as well as for the incorporation of external sources of information. In particular, using a Bayesian trial design, we were able to take into account the results of the parallel trial results when deciding whether to continue each trial beyond the interim stage

Absence of system xc⁻ on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Background: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x(c)- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. Methods: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system x(c)-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT(-/-)) mice and irradiated mice reconstituted in xCT(-/-) bone marrow (BM), to their proper wild type (xCT(+/+)) controls. Results: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT(+/+) mice, xCT(-/-) mice were equally susceptible to EAE, whereas mice transplanted with xCT(-/-) BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. Conclusions: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system x(c)- on immune cells invading the CNS participates to EAE. Since a total loss of system x(c)- had no net beneficial effects, these results have important implications for targeting system x(c)- for treatment of MS

Sex bias in biopsy samples collected from free-ranging dolphins

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in European Journal of Wildlife Research 56 (2010): 151-158, doi:10.1007/s10344-009-0299-7.Biological samples of free-ranging dolphins are increasingly used to gain information on population structure and ecology. In small cetaceans, the gender of individuals usually cannot be determined at sea, and population sex ratio has to be inferred indirectly. We used molecular sexing to determine the gender of 340 biopsy samples of bottlenose dolphins, Tursiops truncatus, spotted dolphins, Stenella frontalis, and common dolphins, Delphinus delphis, collected around the Azores and Madeira. Sex ratio was globally skewed in favor of males, and differed between species and archipelagos. Skew was probably influenced by the selectivity of biopsy collectors and seasonal or year-round predominance of males in natural populations. Skew was also influenced by sampling duration and intensity. In the Azores, when several samples were successively collected within the same group, the proportion of female samples decreased as a function of sample order. This trend indicated a tendency for females to increasingly avoid the boat while samples were being collected. It showed that males and females reacted differently to the perturbation caused by the biopsy sampling process (i.e. sample collection and driving style).Portuguese Foundation for Science and Technology (FCT) and the FEDER program for funding the CETAMARH (POCTI/BSE/38991/01) and the GOLFINICHO (POCI/BIA-BDE/61009/2004) projects, S.Q.'s post-doctoral grants (IMAR/FCT- PDOC-006/2001-MoleGen and SFRH/BPD/19680/2004), M.A.S.'s doctoral (SFRH/BD/8609/2002) and post-doctoral (SFRH/BPD/29841/2006) grants, S.M.'s investigation assistant grant (CETAMARHII/POCTI/BSE/38991/2001) and I.C.'s investigation assistant grants (IMAR/FCT/GOLFINICHO/001/2005 and IMAR/FCT/GOLFINICHO/004/2006). FCT for its pluri-annual funding to Research Unit #531 and the EU funded program Interreg IIIb for funding the MACETUS project (MAC/4.2/M10) as well as R.P. and S.M.’s grants (IMAR/INTERREGIIIb/MACETUS/MAC1/2)

Sociodemographic differences in linkage error: An examination of four large-scale datasets

© 2018 The Author(s). Background: Record linkage is an important tool for epidemiologists and health planners. Record linkage studies will generally contain some level of residual record linkage error, where individual records are either incorrectly marked as belonging to the same individual, or incorrectly marked as belonging to separate individuals. A key question is whether errors in linkage quality are distributed evenly throughout the population, or whether certain subgroups will exhibit higher rates of error. Previous investigations of this issue have typically compared linked and un-linked records, which can conflate bias caused by record linkage error, with bias caused by missing records (data capture errors). Methods: Four large administrative datasets were individually de-duplicated, with results compared to an available 'gold-standard' benchmark, allowing us to avoid methodological issues with comparing linked and un-linked records. Results were compared by gender, age, geographic remoteness (major cities, regional or remote) and socioeconomic status. Results: Results varied between datasets, and by sociodemographic characteristic. The most consistent findings were worse linkage quality for younger individuals (seen in all four datasets) and worse linkage quality for those living in remote areas (seen in three of four datasets). The linkage quality within sociodemographic categories varied between datasets, with the associations with linkage error reversed across different datasets due to quirks of the specific data collection mechanisms and data sharing practices. Conclusions: These results suggest caution should be taken both when linking younger individuals and those in remote areas, and when analysing linked data from these subgroups. Further research is required to determine the ramifications of worse linkage quality in these subpopulations on research outcomes

Memory development: implications for adults recalling childhood experiences in the courtroom

Adults frequently provide compelling, detailed accounts of early childhood experiences in the courtroom. Judges and jurors are asked to decide guilt or innocence based solely on these decades-old memories using 'common sense' notions about memory. However, these notions are not in agreement with findings from neuroscientific and behavioural studies of memory development. Without expert guidance, judges and jurors may have difficulty in properly adjudicating the weight of memory evidence in cases involving adult recollections of childhood experiences

Recombination between Polioviruses and Co-Circulating Coxsackie A Viruses: Role in the Emergence of Pathogenic Vaccine-Derived Polioviruses

Ten outbreaks of poliomyelitis caused by pathogenic circulating vaccine-derived polioviruses (cVDPVs) have recently been reported in different regions of the world. Two of these outbreaks occurred in Madagascar. Most cVDPVs were recombinants of mutated poliovaccine strains and other unidentified enteroviruses of species C. We previously reported that a type 2 cVDPV isolated during an outbreak in Madagascar was co-circulating with coxsackieviruses A17 (CA17) and that sequences in the 3′ half of the cVDPV and CA17 genomes were related. The goal of this study was to investigate whether these CA17 isolates can act as recombination partners of poliovirus and subsequently to evaluate the major effects of recombination events on the phenotype of the recombinants. We first cloned the infectious cDNA of a Madagascar CA17 isolate. We then generated recombinant constructs combining the genetic material of this CA17 isolate with that of the type 2 vaccine strain and that of the type 2 cVDPV. Our results showed that poliovirus/CA17 recombinants are viable. The recombinant in which the 3′ half of the vaccine strain genome had been replaced by that of the CA17 genome yielded larger plaques and was less temperature sensitive than its parental strains. The virus in which the 3′ portion of the cVDPV genome was replaced by the 3′ half of the CA17 genome was almost as neurovirulent as the cVDPV in transgenic mice expressing the poliovirus cellular receptor gene. The co-circulation in children and genetic recombination of viruses, differing in their pathogenicity for humans and in certain other biological properties such as receptor usage, can lead to the generation of pathogenic recombinants, thus constituting an interesting model of viral evolution and emergence