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This research was carried out to assess the feasibility of studying the effects of introducing copayments in primary medical care via studying the effects of copayments in primary dental care. Quantitative methods were used to investigate the impact of primary dental care copayments on patients and to compare predictors of primary medical and dental care uptake. Qualitative methods were used to investigate attitudes towards copayments for NHS primary health services and their extension to include primary medical consultations. Regression models, chi-square analyses and ANOVA were applied to the England and Wales sub-sample of nationally representative self-report data from the 1998 Adult Dental Health Survey (ADHS) (n=3628) to investigate the impact of copayments on primary dental care uptake. Regression models and chi-square analyses were applied to the England and Wales sub-sample of nationally representative self-report data from the 1997/98 British Household Panel Survey (BHPS) (n=8526) and the 1998 ADHS (n=3641) to compare predictors of primary medical and dental consultations. Semi- structured interviews were undertaken in Bristol and Somerset with purposively sampled frequent and infrequent primary medical care users (n=19). Predictors of primary medical and dental care utilisation differed across predisposing, enabling and illness level factors. Private and NHS dental copayments were perceived to be expensive and this perception was associated with lower preventive-led dental consultation rates, but not with treatment-led consultation rates. Copayments for services affected the nature of the patient-practitioner relationship. Findings were inconclusive regarding the effect of copayment exemption status on people's decisions to consult a dentist and on dental treatments received. It was not feasible to study the effects of introducing copayments in primary medical care via studying the effects of copayments in primary dental care.

The uterus is the organ for embryo implantation and fetal development. Most current models of the uterus are centred around capturing its function during later stages of pregnancy to increase the survival in pre-term births. However, in vitro models focusing on the uterine tissue itself would allow modelling of pathologies including endometriosis and uterine cancers, and open new avenues to investigate embryo implantation and human development. Motivated by these key questions, we discuss how stem cell-based uteri may be engineered from constituent cell parts, either as advanced self-organising cultures, or by controlled assembly through microfluidic and print-based technologies., Bergmann et al. discuss the construction of synthetic uteri to model the earliest stages of human embryogenesis and associated pathologies. They highlight the constituent components from which a synthetic uterus may be engineered, propose a modular approach to assembling synthetic uteri and discuss how these technologies can shed light on implantation failure and uterine pathologies.

Mammalian embryogenesis relies on glycolysis and oxidative phosphorylation to balance the generation of biomass with energy production. However, the dynamics of metabolic regulation in the postimplantation embryo in vivo have remained elusive due to the inaccessibility of the implanted conceptus for biochemical studies. To address this issue, we compiled single-cell embryo profiling data in six mammalian species and determined their metabolic dynamics through glycolysis and oxidative phosphorylation associated gene expression. Strikingly, we identify a conserved switch from bivalent respiration in the late blastocyst towards a glycolytic metabolism in early gastrulation stages across species, which is independent of embryo implantation. Extraembryonic lineages followed the dynamics of the embryonic lineage, except visceral endoderm. Finally, we demonstrate that in vitro primate embryo culture substantially impacts metabolic gene regulation by comparison to in vivo samples. Our work reveals a conserved metabolic programme despite different implantation modes and highlights the need to optimise postimplantation embryo culture protocols.

Gastrulation controls the emergence of cellular diversity and axis patterning in the early embryo. In mammals, this transformation is orchestrated by dynamic signalling centres at the interface of embryonic and extraembryonic tissues1-3. Elucidating the molecular framework of axis formation in vivo is fundamental for our understanding of human development4-6 and to advance stem-cell-based regenerative approaches7. Here we illuminate early gastrulation of marmoset embryos in utero using spatial transcriptomics and stem-cell-based embryo models. Gaussian process regression-based 3D transcriptomes delineate the emergence of the anterior visceral endoderm, which is hallmarked by conserved (HHEX, LEFTY2, LHX1) and primate-specific (POSTN, SDC4, FZD5) factors. WNT signalling spatially coordinates the formation of the primitive streak in the embryonic disc and is counteracted by SFRP1 and SFRP2 to sustain pluripotency in the anterior domain. Amnion specification occurs at the boundaries of the embryonic disc through ID1, ID2 and ID3 in response to BMP signalling, providing a developmental rationale for amnion differentiation of primate pluripotent stem cells (PSCs). Spatial identity mapping demonstrates that primed marmoset PSCs exhibit the highest similarity to the anterior embryonic disc, whereas naive PSCs resemble the preimplantation epiblast. Our 3D transcriptome models reveal the molecular code of lineage specification in the primate embryo and provide an in vivo reference to decipher human development.

MotivationA common class of behaviour encountered in the biological sciences involves branching and recombination. During branching, a statistical process bifurcates resulting in two or more potentially correlated processes that may under-go further branching; the contrary is true during recombination, where two or more statistical processes converge into one. A key objective is to identify the time of this bifurcation (branch time) from time series measurements e.g., comparing a control time series with a perturbed time series. Whilst statistical treatments for the two branch (control versus treatment) case exists, the ability to infer more complex branching structure from time series data remains open. Gaussian processes (GPs) represents an ideal framework for such analysis, allowing for nonlinear regression that includes a rigorous treatment of uncertainty. Currently, however, GP models only exist for two-branch systems. Here we highlight how arbitrarily complex branching processes can be built using the correct composition of covariance functions within a GP framework, thus outlining a general framework for the treatment of branching and recombination in the form of branch-recombinant Gaussian processes (B-RGPs). We first demonstrate the performance of B-RGPs compared to a variety of existing regression approaches, and demonstrate robustness to model misspecification. B-RGPs are then used to investigate the branching patterns ofArabidopsis thalianagene expression following inoculation with the hemibotrophic bacteria,Pseudomonas syringae DC3000, and a disarmed mutant strain, hrpA. By grouping genes according to the number of branches, we could naturally separate out genes involved in basal immune response from those subverted by the virulent strain, and show enrichment for targets of pathogen protein effectors. Finally, we identify two early branching genes WRKY11 and WRKY17, and showed that groups of genes that branched at similar times to WRKY11/17 were enriched for W-box binding motifs, and overrepresented for genes differentially expressed in WRKY11/17 knockouts, suggesting that branch time could be used for identifying direct and indirect binding targets of key transcription factors.Software is available from:https://github.com/cap76/BranchingGPs.

Meiosis is the cell division that halves the genetic component of diploid cells to form gametes or spores. To achieve this, meiotic cells undergo a radical spatial reorganisation of chromosomes. This reorganisation is a prerequisite for the pairing of parental homologous chromosomes and the reductional division, which halves the number of chromosomes in daughter cells. Of particular note is the change from a centromere clustered layout (Rabl configuration) to a telomere clustered conformation (bouquet stage). The contribution of the bouquet structure to homologous chromosome pairing is uncertain. We have developed a new in silico model to represent the chromosomes of Saccharomyces cerevisiae in space, based on a worm-like chain model constrained by attachment to the nuclear envelope and clustering forces. We have asked how these constraints could influence chromosome layout, with particular regard to the juxtaposition of homologous chromosomes and potential nonallelic, ectopic, interactions. The data support the view that the bouquet may be sufficient to bring short chromosomes together, but the contribution to long chromosomes is less. We also find that persistence length is critical to how much influence the bouquet structure could have, both on pairing of homologues and avoiding contacts with heterologues. This work represents an important development in computer modeling of chromosomes, and suggests new explanations for why elucidating the functional significance of the bouquet by genetics has been so difficult., Author Summary Organisms store their genetic material in the form of chromosomes that must be replicated and shared out during cell division. In sexual reproduction the cell division, called meiosis, halves the number of chromosomes to form gametes. This halving requires a complex reorganisation of chromosomes. Each gamete receives one maternal or one paternal copy of every chromosome. This requires a pairing process between the maternal and paternal chromosomes of each type. Once paired the two chromosomes are organised in space to bias subsequent movement in opposite directions when the nucleus divides. How chromosomes pair is of great importance to understanding fertility, and manipulating chromosomes in crops species, for which it is desirable to breed in new genes to improve hardiness or yield. We have modelled chromosomes in 3-dimensions based on the experimental organism Saccharomyces cerevisiae. We used our model to ask if various physical features of chromosomes might influence their ability to pair. We found that binding chromosome ends to the nuclear wall and pushing those ends together helps to encourage pairing along the length of chromosomes. It has long been known this special chromosome organisation occurs in live cells, but the significance of it has been difficult to determine.