Model of Tooth Morphogenesis Predicts Carabelli Cusp Expression, Size, and Symmetry in Humans

The patterning cascade model of tooth morphogenesis accounts for shape development through the interaction of a small number of genes. In the model, gene expression both directs development and is controlled by the shape of developing teeth. Enamel knots (zones of nonproliferating epithelium) mark the future sites of cusps. In order to form, a new enamel knot must escape the inhibitory fields surrounding other enamel knots before crown components become spatially fixed as morphogenesis ceases. Because cusp location on a fully formed tooth reflects enamel knot placement and tooth size is limited by the cessation of morphogenesis, the model predicts that cusp expression varies with intercusp spacing relative to tooth size. Although previous studies in humans have supported the model's implications, here we directly test the model's predictions for the expression, size, and symmetry of Carabelli cusp, a variation present in many human populations.In a dental cast sample of upper first molars (M1s) (187 rights, 189 lefts, and 185 antimeric pairs), we measured tooth area and intercusp distances with a Hirox digital microscope. We assessed Carabelli expression quantitatively as an area in a subsample and qualitatively using two typological schemes in the full sample. As predicted, low relative intercusp distance is associated with Carabelli expression in both right and left samples using either qualitative or quantitative measures. Furthermore, asymmetry in Carabelli area is associated with asymmetry in relative intercusp spacing.These findings support the model's predictions for Carabelli cusp expression both across and within individuals. By comparing right-left pairs of the same individual, our data show that small variations in developmental timing or spacing of enamel knots can influence cusp pattern independently of genotype. Our findings suggest that during evolution new cusps may first appear as a result of small changes in the spacing of enamel knots relative to crown size

Design and implementation of a biomolecular concentration tracker

As a field, synthetic biology strives to engineer increasingly complex artificial systems in living cells. Active feedback in closed loop systems offers a dynamic and adaptive way to ensure constant relative activity independent of intrinsic and extrinsic noise. In this work, we use synthetic protein scaffolds as a modular and tunable mechanism for concentration tracking through negative feedback. Input to the circuit initiates scaffold production, leading to colocalization of a two-component system and resulting in the production of an inhibitory antiscaffold protein. Using a combination of modeling and experimental work, we show that the biomolecular concentration tracker circuit achieves dynamic protein concentration tracking in Escherichia coli and that steady state outputs can be tuned

An orthogonal C-H borylation - cross-coupling strategy for the preparation of tetrasubstituted "A(2)B(2)''-chrysene derivatives with tuneable photophysical properties

Cl-substituents serve as a functionalisable regiocontrol element for the orthogonal functionalisation of chrysene.</p

Exome sequencing in classic hairy cell leukaemia reveals widespread variation in acquired somatic mutations between individual tumours apart from the signature BRAF V(600)E lesion

In classic Hairy cell leukaemia (HCLc), a single case has thus far been interrogated by whole exome sequencing (WES) in a treatment naive patient, in which BRAF V(600)E was identified as an acquired somatic mutation and confirmed as occurring near-universally in this form of disease by conventional PCR-based cohort screens. It left open however the question whether other genome-wide mutations may also commonly occur at high frequency in presentation HCLc disease. To address this, we have carried out WES of 5 such typical HCLc cases, using highly purified splenic tumour cells paired with autologous T cells for germline. Apart from BRAF V(600)E, no other recurrent somatic mutation was identified in these HCLc exomes, thereby excluding additional acquired mutations as also prevalent at a near-universal frequency in this form of the disease. These data then place mutant BRAF at the centre of the neoplastic drive in HCLc. A comparison of our exome data with emerging genetic findings in HCL indicates that additional somatic mutations may however occur recurrently in smaller subsets of disease. As mutant BRAF alone is insufficient to drive malignant transformation in other histological cancers, it suggests that individual tumours utilise largely differing patterns of genetic somatic mutations to coalesce with BRAF V(600)E to drive pathogenesis of malignant HCLc disease

Carbon on the Northwest European Shelf: Contemporary Budget and Future Influences

A carbon budget for the northwest European continental shelf seas (NWES) was synthesized using available estimates for coastal, pelagic and benthic carbon stocks and flows. Key uncertainties were identified and the effect of future impacts on the carbon budget were assessed. The water of the shelf seas contains between 210 and 230 Tmol of carbon and absorbs between 1.3 and 3.3 Tmol from the atmosphere annually. Off-shelf transport and burial in the sediments account for 60–100 and 0–40% of carbon outputs from the NWES, respectively. Both of these fluxes remain poorly constrained by observations and resolving their magnitudes and relative importance is a key research priority. Pelagic and benthic carbon stocks are dominated by inorganic carbon. Shelf sediments contain the largest stock of carbon, with between 520 and 1600 Tmol stored in the top 0.1 m of the sea bed. Coastal habitats such as salt marshes and mud flats contain large amounts of carbon per unit area but their total carbon stocks are small compared to pelagic and benthic stocks due to their smaller spatial extent. The large pelagic stock of carbon will continue to increase due to the rising concentration of atmospheric CO2, with associated pH decrease. Pelagic carbon stocks and flows are also likely to be significantly affected by increasing acidity and temperature, and circulation changes but the net impact is uncertain. Benthic carbon stocks will be affected by increasing temperature and acidity, and decreasing oxygen concentrations, although the net impact of these interrelated changes on carbon stocks is uncertain and a major knowledge gap. The impact of bottom trawling on benthic carbon stocks is unique amongst the impacts we consider in that it is widespread and also directly manageable, although its net effect on the carbon budget is uncertain. Coastal habitats are vulnerable to sea level rise and are strongly impacted by management decisions. Local, national and regional actions have the potential to protect or enhance carbon storage, but ultimately global governance, via controls on emissions, has the greatest potential to influence the long-term fate of carbon stocks in the northwestern European continental shelf

The PSEN1 E280G mutation leads to increased amyloid-β43 production in induced pluripotent stem cell neurons and deposition in brain tissue

Mutations in the presenilin 1 gene, PSEN1, which cause familial Alzheimer’s disease alter processing of amyloid precursor protein, leading to the generation of various amyloid-β peptide species. These species differ in their potential for aggregation. Mutation-specific amyloid-β peptide profiles may thereby influence pathogenicity and clinical heterogeneity. There is particular interest in comparing mutations with typical and atypical clinical presentations, such as E280G. We generated PSEN1 E280G mutation induced pluripotent stem cells from two patients and differentiated them into cortical neurons, along with previously reported PSEN1 M146I, PSEN1 R278I and two control lines. We assessed both the amyloid-β peptide profiles and presenilin 1 protein maturity. We also compared amyloid-β peptide profiles in human post-mortem brain tissue from cases with matched mutations. Amyloid-β ratios significantly differed compared with controls and between different patients, implicating mutation-specific alterations in amyloid-β ratios. Amyloid-β42:40 was increased in the M146I and both E280G lines compared with controls. Amyloid-β42:40 was not increased in the R278I line compared with controls. The amyloid-β43:40 ratio was increased in R278I and both E280G lines compared with controls, but not in M146I cells. Distinct amyloid-β peptide patterns were also observed in human brain tissue from individuals with these mutations, showing some similar patterns to cell line observations. Reduced presenilin 1 maturation was observed in neurons with the PSEN1 R278I and E280G mutations, but not the M146I mutation. These results suggest that mutation location can differentially alter the presenilin 1 protein and affect its autoendoproteolysis and processivity, contributing to the pathological phenotype. Investigating differences in underlying molecular mechanisms of familial Alzheimer’s disease may inform our understanding of clinical heterogeneity